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WO2009137103A2 - Anti-cancer/anti-viral compounds and methods of use - Google Patents

Anti-cancer/anti-viral compounds and methods of use Download PDF

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Publication number
WO2009137103A2
WO2009137103A2 PCT/US2009/002883 US2009002883W WO2009137103A2 WO 2009137103 A2 WO2009137103 A2 WO 2009137103A2 US 2009002883 W US2009002883 W US 2009002883W WO 2009137103 A2 WO2009137103 A2 WO 2009137103A2
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WIPO (PCT)
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alkyl
aryl
heteroaryl
cycloalkyl
heterocyclyl
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PCT/US2009/002883
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French (fr)
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WO2009137103A3 (en
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Donald D. Ourth
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT

Definitions

  • the invention relates to compounds, compositions and methods for inhibiting, preventing and/or treating cancer and/or viral, helminthic, fungal, microbial, bacterial and/or protozoal infection, and/or insecticidal activity.
  • Cancer including those cancers thought to be caused by viruses, is a disease that afflicts many people and is a leading cause of death in humans and non-human animals. Cancer typically involves uncontrolled growth of cells that then creates many new cells. Many anti-cancer drugs are agents that inhibit or stop cell growth. Such chemotherapeutic agents have improved the survival rate of patients having cancer. However, the serious side effects associated with many chemotherapeutic agents limits their usage and undermines the health of patients already weakened by cancer. Thus, new agents are needed that exhibit enhanced selectivity for cancer cells or that are capable of controlling proliferation of cancerous cells with limited side effects.
  • Viral infections are among the leading causes of death with millions of deaths each year being directly attributable to several viruses including hepatitis and HIV.
  • Many of the existing anti- virals cause adverse or undesirable side-effects and most effective therapies (such as vaccination) are highly specific for only a single strain of virus. Frequently a virus undergoes mutation such that it becomes resistant to either the drug or vaccine.
  • therapies such as vaccination
  • the Heliothis virescens hemolymph (blood) was found to have antiviral activity (Ourth, D. D., Renis, H. E. Comp. Biochem. Physiol., 105B, 719-723, 1993).
  • the hemolymph antiviral factor was antiviral against Herpes Simplex Virus- 1 (SI of 1 10), Herpes Simplex Virus-2 (SI of 1 10), Vesicular Stomatitis Virus (SI of 45), Coxsackie B3 (SI of 20), Sindbis (SI of 20), and Parainfluenza-3 (SI of 16) DNA and RNA viruses.
  • One embodiment provides a compound of formula (XX):
  • X is C 6 -C 25 alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (Ci-C 6 )alkyl;
  • R 1 and R 2 independently comprises H or (C
  • R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted (e.g., two or more) with halo, hydroxy, CO 2 Y, CONYY', NYY 1 , oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein Y and Y' independently at each occurrence comprises H, or (C
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-Cio)alkyl, (C 2 -C i O )alkenyl, (C 2 -C , 0 )alkynyl, (Ci-Cio)haloalkyl, (C 3 -Ci 0 )cycloalkyl, (C 3 - Cio)cycIoalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (C r C 6 )haloalkyl, (C r C 6 )haloalkoxy, carboxamido, heterocyclyl,
  • X 1 when X 1 is C 6 -C 25 alkylcarbonyl, X 3 is not Ala, X 4 is not VaI and X 5 is not Ala. In another embodiment, when X 1 is myristoyl or palmitoyl, X 3 is not Ala, X 4 is not VaI and X 5 is not Ala.
  • the steroid is cholesterol, vitamin A, or vitamin D.
  • X 3 -X 5 are independently any non-polar amino acid and X 6 is absent. In another embodiment, X 6 is any non-polar amino acid.
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • the compound forms a dimer.
  • X 1 is myristoyl or palmitoyl.
  • X 2 is cysteine.
  • R 1 and R 2 are methyl.
  • R 3 is OMe.
  • X'-X 6 are independently either absent or any number of (e.g., one or more) O, S, CR, NR, or amino acids, all of which may be optionally independently substituted (e.g., optionally independently substituted with 1-4 (Ci-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C 6 )alkyl, OR, halo, NR 2 , or carboxyamido).
  • composition comprising a compound provided herein and a pharmaceutically acceptable carrier.
  • unit dosage form comprising a compound provided herein and a pharmaceutically acceptable carrier.
  • One embodiment provides a method to inhibit replication of a virus in a cell comprising contacting said cell with a compound provided herein in an amount effective to inhibit the replication of the virus in said cell.
  • the virus is human immunodeficiency virus (HIV), herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, Sindbis virus, or Epstein Barr Virus (EBV).
  • Another embodiment provides a method to inhibit replication of a virus in a cell comprising contacting said cell with a compound of formula (XX):
  • X 1 is C 6 -C 2 salkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X D are any amino acid or absent;
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (C)-C 6 )alkyl;
  • R 1 and R 2 are independently H or (C)-C 4 )alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein Y and Y' independently at each occurrence comprises H, or (Ci-C 6 )alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-Cio)alkyl, (C 2 -C i O )alkenyl, (C 2 -C, 0 )alkynyl, (Ci-Cio)haloalkyl, (C 3 -C,o)cycloalkyl, (C 3 - Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (C r C 6 )haloalkyl, (C
  • the virus is not herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or Sindbis viruses.
  • the virus is an Epstein Barr Virus (EBV).
  • the virus is human immunodeficiency virus (HIV), herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, Sindbis virus, or Epstein Ban- Virus (EBV).
  • HAV human immunodeficiency virus
  • herpes simplex virus-1 herpes simplex virus-1
  • herpes simplex virus-2 herpes simplex virus-2
  • vesicular stomatitis virus parainfluenza-3
  • coxsackie B3, Sindbis virus or Epstein Ban- Virus (EBV).
  • Another embodiment provides a method to inhibit a viral infection in vitro or in vivo comprising contacting a sample in need of such treatment with a compound of formula (XX):
  • X is C 6 -C 25 alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent; X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9,
  • R is independently at each occurrence H or (Ci-C 6 )alkyl;
  • R 1 and R 2 are independently H or (Ci-C 4 )alkyl or
  • R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (C ⁇ -C ⁇ o)alkyl, (C 2 -C] 0 )alkenyl, (C 2 -Ci 0 )alkynyl, (Ci-Cio)haloalkyl, (C 3 -C
  • C 6 haloalkoxy, or carboxyamido, or any combination thereof, or two R B together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of R B is optionally substituted with 1-4 (Ci-C 6 )alkyl, OR, halo, NR 2 , nitro, (C]-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, or carboxyamido, or any combination thereof;
  • Q 1 , Q 2 , Q 3 and Q 4 are each independently CR 7 , N, O, or S(0) p wherein p is O, 1 , or 2; each R 7 is independently H, halo, N(R B ) 2 , (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 3 - C 7 )cycloalkyl, aryl, heteroaryl, or R 8 , wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R 7 is optionally independently substituted with 1-4 (Ci-C 6 )alkyl, halo, OR, NR B 2 , (C
  • -C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, carboxamido, or R 8 , or any combination thereof, wherein each R comprises cyano, CO 2 R, or a group of formula -C( X )N(R ) 2
  • the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or Sindbis virus infection.
  • the virus is an Epstein Barr Virus (EBV).
  • the contacting is in vivo.
  • Another embodiment provides a method to treat a viral infection comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.
  • the virus is human immunodeficiency virus (HIV), herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, Sindbis virus, or Epstein Barr Virus (EBV).
  • HIV human immunodeficiency virus
  • XX a compound of formula (XX):
  • X is C 6 -C 25 alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent;
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (Ci-C 6 )alkyl;
  • R 1 and R 2 are independently H or (Ci-C 4 )alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl,
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-C ⁇ o)alkyl, (C 2 -C,o)alkenyl, (C 2 -C 10 )alkynyl, (C,-C, 0 )haloalkyl, (C 3 -C, 0 )cycloalkyl, (C 3 - Cio)cycloalkyl(Ci-C ⁇ o)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (C,-C 6 )haloalkyl, (C r C 6 )haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroary
  • C 6 haloalkoxy, or carboxyamido, or any combination thereof, or two R B together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of R B is optionally substituted with 1-4 (Ci-C 6 )alkyl, OR, halo, NR 2 , nitro, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, or carboxyamido, or any combination thereof;
  • Q 1 , Q 2 , Q 3 and Q 4 are each independently CR 7 , N, O, or S(0) p wherein p is O, 1 , or 2; each R 7 is independently H, halo, N(R B ) 2 , (Ci-C 6 )alkyl, (C,-C 6 )haloalkyl, (C 3 - C 7 )cycloalkyl, aryl, heteroaryl, or R 8 , wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R 7 is optionally independently substituted with 1 -4 (C
  • -C 6 )alkyl, halo, OR, NR 2 , (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, carboxamido, or R , or any combination thereof, wherein each R 8 comprises cyano, CO 2 R, or a group of formula -C( X 8 )N(R 9 )
  • C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ci-C 6 )alkyl, OR, halo, NR 2 , nitro, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, or carboxyamido, or two R 9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O) 2 , and NR B , optionally independently substituted with 1-4 (Ci-C 6 )alkyl, OR, halo, NR 2 , nitro, (C
  • the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or Sindbis virus infection.
  • the virus is an Epstein Barr Virus (EBV).
  • the subject is a mammal, including a human.
  • Another embodiment provides a compound disclosed herein formulated with a pharmaceutically acceptable carrier. Another embodiment provides the administration of a second active ingredient.
  • One embodment provides a method to inhibit tumor growth in vitro or in vivo comprising contacting a cell in need of such treatment with a compound of formula (XX):
  • X 1 is Q-C ⁇ alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent;
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (Ci-C 6 )alkyl;
  • R 1 and R 2 are independently H or (Ci-C 4 )alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl/ heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein Y and Y' independently at each occurrence comprises H, or (Ci-C 6 )alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-Cio)alkyl, (C 2 -C 10 )alkenyl, (C 2 -C , 0 )alkynyl, (Ci-Cio)haloalkyl, (C 3 -C, 0 )cycloalkyl, (C 3 - Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (C,-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (C,-C 6 )haloalkyl, (C,-C 6 )haloalkoxy, carboxamido, heterocyclyl, aryl, or hetero
  • the contacting is in vivo.
  • the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal.
  • One embodiment provides a method to treat symptoms of cancer in a subject comprising administering to a subject in need thereof an effective amount of a compound of formula (XX):
  • X 1 is C 6 -C 25 alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (Ci-C 6 )alkyl
  • R 1 and R 2 are independently H or (Ci-C 4 )alkyl or or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein Y and Y' independently at each occurrence comprises H, or (Ci-C 6 )alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-Cio)alkyl, (C 2 -Ci 0 )alkenyl, (C 2 -C, 0 )alkynyI, (C,-Ci 0 )haloalkyl, (C 3 -C, 0 )cycloalkyl, (C 3 - C
  • Q 1 , Q 2 , Q 3 and Q 4 are each independently CR 7 , N, O, or S(0) p wherein p is O, 1 , or 2; each R 7 is independently H, halo, N(R B ) 2 , (C,-C 6 )alkyl, (C r C 6 )haloalkyl, (C 3 -
  • Another embodiment provides a method to inhibit neoplastic disease in a subject comprising administering to a subject in need thereof an effective amount of a compound of formula (XX):
  • X 1 is C 6 -C 25 alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent;
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (C
  • R 1 and R 2 are independently H or (Ci-C 4 )alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloal
  • the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T- cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma, including Burkitt's lymphoma.
  • the subject is a mammal, including a human.
  • the compound is formulated with a pharmaceutically acceptable carrier.
  • a second active ingredient is administered.
  • One embodiment provides a compound of formula (XX):
  • X 1 is C 6 -C 25 alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (Ci-C 6 )alkyl
  • R 1 and R 2 are independently H or (Ci-Gj)alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein Y and Y 1 independently at each occurrence comprises H, or (Ci-C 6 )alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (C ⁇ -Cio)alkyl, (C 2 -C i O )alkenyl, (C 2 -Ci 0 )alkynyl, (C,-C
  • Q 1 , Q 2 , Q 3 and Q 4 are each independently CR 7 , N, O, or S(0) p wherein p is O, 1 , or 2; each R 7 is independently H, halo, N(R B ) 2 , (C,-C 6 )alkyl, (C,-C 6 )haloalkyl, (C 3 - C 7 )cycloalkyl, aryl, heteroaryl, or R 8 , wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R 7 is optionally independently substituted with 1-4 (C
  • -C 6 )alkyl, halo, OR, NR 2 , (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, carboxamido, or R , or any combination thereof, wherein each R 8 comprises cyano, CO 2 R, or a group of formula -C( X 8 )N(R 9 ) 2
  • X 1 is myristoyl or palmitoyl
  • X 3 is not Ala
  • X 4 is not VaI
  • X 5 is not Ala.
  • the medical therapy is treatment of cancer. In another embodiment, the medical therapy is treatment or prevention of a viral infection.
  • X 1 is C ⁇ -C ⁇ alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent;
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (C
  • R 1 and R 2 are independently H or (Ci-C 4 )alkyl or
  • R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein Y and Y' independently at each occurrence comprises H, or (Ci-C 6 )alkyl which can be optionally substituted by hydroxyl, amino, COOY, hetero
  • R 3 is any carboxy protecting group
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (C r Ci 0 )alkyl,
  • the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or Sindbis virus infection.
  • the viral infection is an Epstein Barr Virus (EBV) infection.
  • HSV-2 herpes simplex virus-2
  • VSV vesicular stomatitis virus
  • EBV Epstein Barr Virus
  • X is C6-C 2 5alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or
  • X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent;
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (Ci-C 6 )alkyl;
  • R 1 and R 2 are independently H or (C r C 4 )alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl
  • R 3 is any carboxy protecting group
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-Cio)alkyl, (C 2 -Ci 0 )alkenyl, (C 2 -C, 0 )alkynyl, (Ci-Cio)haloalkyl, (C 3 -Ci 0 )cycloalkyl, (C 3 -
  • Ci 0 cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (C,-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (C,-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C 6 )alkyl, OR, halo, NR 2 , or carboxyamido; wherein R 6 is (Ci-C 6 )alkyl, OR A , or N(R B ) 2 , R A independently at each occurrence comprises H, (Ci-Cio)
  • Q 1 , Q 2 , Q 3 and Q 4 are each independently CR 7 , N, O, or S(0) p wherein p is O, 1 , or 2; each R 7 is independently H, halo, N(R B ) 2 , (C,-C 6 )alkyl, (C,-C 6 )haloalkyl, (C 3 - C 7 )cycloalkyl, aryl, heteroaryl, or R 8 , wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R 7 is optionally independently substituted with 1 -4 (Ci-C 6 )alkyl, halo, OR, NR B 2 , (C
  • -C 6 )haloalkyl, (Cj-C 6 )haloalkoxy, carboxamido, or R 8 , or any combination thereof, wherein each R 8 comprises cyano, CO 2 R, or a group of formula -C( X 8 )N(R 9
  • the viral infection is a HIV, herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, Sindbis virus, or EBV infection.
  • X 1 is C 6 -C 25 alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid;
  • X 2 is any amino acid or absent or X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid or absent;
  • X 6 is at least one amino acid or absent (e.g., X 6 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
  • R is independently at each occurrence H or (Ci-C 6 )alkyl;
  • R 1 and R 2 are independently H or (Ci-C 4 )alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocycly
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-Cio)alkyl, (C 2 -C 10 )alken ⁇ l, (C 2 -Ci 0 )alkynyl, (Ci-C 10 )haloalkyl, (C 3 -C 10 )cycloalkyl, (C 3 - C ⁇ o)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (Ci-C 6 )haloalkyl, (C
  • C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C,-C 6 )alkyl, OR, halo, NR 2 , nitro, (C,-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, or carboxyamido, or two R 9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O) 2 , and NR B , optionally independently substituted with 1 -4 (Ci-C 6 )alkyl, OR, halo, NR 2 , nitro, (Ci-C 6 )haloalkyl, (C,-C 6 )haloalkoxy, or carboxya
  • the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal.
  • the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy-cell leukemia or non- Hodgkin's lymphoma, including Burkitt's lymphoma.
  • a method to treat a fungal infection comprising administering an effective amount of a compound of the invention (e.g., a comound of formula XX) to a subject in need thereof.
  • Another embodiment provides a method to treat a fungal (e.g., pathogenic Candida (yeast) species, and/or Aspergillus species, Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, Cryptococcus gattii, Histoplasma capsulatum, Pneumocystis jirovecii, andor Stachybotrys chartarum), helminthic (e.g,.
  • a fungal e.g., pathogenic Candida (yeast) species, and/or Aspergillus species, Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, Cryptococcus gattii, Histoplasma capsulatum, Pneumocystis jirovecii, andor Stachybotrys chartarum
  • helminthic e.g,.
  • parasitic worms including cestodes (e.g., tapeworms), nematodes (e.g., whipworms, hookworms, pinworms, ascarids, filarids, Trichinella spiralis (trichina worm (trichinosis)), baylisascaris, haemonchus contortus or entomopathogenic nematodes), or trematodes (e.g., flukes - tissue flukes which infect, for example, the bile ducts, lungs (e.g., Paragonimus westermani), liver (e.g., Clonorchis sinensis and Fasciola hepatica), or _ other biological tissues or blood flukes)), bacterial (e.g., tuberculosis (TB) bacterium or pathogenic bacterium from the following genuses: Bacillus, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia, Clo
  • is palmitoyl, a transporter peptide sequence; HIV- TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid;
  • X 2 is cysteine, serine, or homoalanine; or
  • Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine);
  • X 6 is either absent or at least one nonpolar amino acid (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 1
  • the steroid is cholesterol, vitamin A, or vitamin D or terpenoid lipid.
  • the compound forms a dimer, while in other embodiments the compound is monomer.
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine.
  • X 6 is absent.
  • (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
  • One embodiment provides a composition comprising the compound of formula (VII) and a pharmaceutically acceptable carrier. Another embodiment provides a method of making a composition comprising admixing a compound of the invention with a pharmaceutically acceptable carrier. Another embodiment provides a unit dosage form comprising a compound of formula (VII) and a pharmaceutically acceptable carrier.
  • Another embodiment provides a method to inhibit replication of a virus in a cell comprising contacting said cell with a compound of formula (I): Myristoyl-Cys-X]-X 2 -X 3 X4-Tyr-(Z)His-OMe (I) in an amount effective to inhibit the replication of the virus in said cell, provided the virus is not HIV or herpes simplex virus-1 (HSV-I), wherein Xi- X 3 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X 4 is either absent or at least one nonpolar amino acid (X 4 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or
  • Xi is alanine
  • X 2 is valine and X 3 is alanine.
  • X 4 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the virus is not herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or Sindbis viruses.
  • the virus is EBV.
  • Another embodiment provides a method to inhibit the replication of a virus in a cell comprising contacting said cell with a compound of formula (VII): Xi-X 2 - X 3 -X 4 - Xs-X 6 -Ty r-(Z)Hi s-OMe (VII), wherein Xj is palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X 2 is cysteine, serine, homoalanine; or X
  • the virus is HIV, herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfIuenza-3, coxsackie B3, Sindbis virus, or EBV.
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine.
  • X 6 is absent.
  • (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
  • Another embodiment provides a method for inhibiting a viral infection in vitro or in vivo comprising contacting a sample, cell or subject in need of such treatment with a compound of formula (I): Myristoyl-Cys-X
  • Xi is alanine
  • X 2 is valine and X 3 is alanine.
  • X 4 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or Sindbis virus infection.
  • the viral infection is an EBV infection.
  • One embodiment provides a method for inhibiting a viral infection in vitro or in vivo comprising contacting a sample, cell or subject in need of such treatment with a compound of formula (VII): X,-X 2 -X 3 -X 4 -X 5 -X 6 -Tyr-(Z)His-OMe (VII), wherein X, is palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X 2 is cysteine, serine, homoalanine; or Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X 3 -X 5 are independently any nonpolar amino acid (such as tryptophan, glycine,
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the contacting is in vivo.
  • the viral infection is an HIV, herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, Sindbis virus, or EBV infection.
  • Another embodiment provides a method of treating a viral infection in a subject, comprising administering a compound of formula (I) to the subject Myristoyl-Cys-Xi-X 2 - X 3 -X 4 -TVr-(Z)HiS-OMe (I), provided the viral infection is not a HIV or herpes simplex virus-1 (HSV-I) infection, wherein XpX 3 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X 4 is either absent or at least one nonpolar amino acid (e.g., X 4 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and
  • is alanine
  • X 2 is valine and X 3 is alanine.
  • X 4 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus, parainfluenza-3, coxsackie B3, or Sindbis virus infection.
  • the viral infection is an EBV infection.
  • Another embodiment provides a method of treating a viral infection in a subject, comprising administering a compound of formula (VII) to the subject: X)-X 2 -X 3 -X 4 -Xs- X 6 -Tyr-(Z)His-OMe (VII), wherein Xi is palmitoyl, a transporter peptide sequence; HIV- TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X 2 is cysteine, serine, homoalanine; or Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X 3 -X 5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, pro
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the viral infection is an HIV, herpes simplex virus- 1, herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, Sindbis virus, or EBV infection.
  • Another embodiment provides a method of inhibiting tumor growth in vitro or in vivo comprising the step of contacting a sample, cell or subject in need of such treatment with a compound of formula (VII): X, -X 2 - X 3 -X 4 -X 5 -X 6 -Tyr-(Z)His-OMe (VII), wherein Xi is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X 2 is cysteine, serine, homoalanine; or Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X 3 -X 5 are independently any nonpolar amino acid (such as try
  • the contacting is in vivo.
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine.
  • X 6 is absent.
  • (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
  • the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal.
  • Another embodiment provides a method of treating the symptoms or effects of cancer in a subject which comprises administering to said subject a compound of formula (VlI): Xi-X 2 - X 3 -X 4 -X 5 -X 6 -Tyr-(Z)His-OMe (VII), wherein X, is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X 2 is cysteine, serine, homoalanine; or Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X 3 -X 5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine,
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl). In another embodiment, (Z) is (1,3 dimethyl).
  • Another embodiment provides a method of inhibiting neoplastic diseases in a subject in need of such treatment comprising administering to said subject a compound of formula (VII): X 1 -X 2 - X 3 -X 4 -X 5 -X 6 -Tyr-(Z)His-OMe (VIII), wherein Xi is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X 2 is cysteine, serine, homoalanine; or X) and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X 3 -X 5 are independently any nonpolar amino acid (such as tryptophan, glycine,
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
  • the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma.
  • the non- Hodgkin's lymphoma is Burkitt's lymphoma.
  • the subject is a mammal, such as a human.
  • the sample includes bodily fluid or cells, such as blood cells, tumor cells and/or cells infected by a virus, including but not limited to eukaryotic cells, such as human cells.
  • the compound is formulated with a pharmaceutically acceptable carrier. In other embodiments, the compound is further formulated with a second active ingredient.
  • Another embodiment provides a compound of a compound of formula (VII): Xi-
  • X 2 - X 3 -X 4 -X 5 -X 6 -Tyr-(Z)His-OMe VII
  • Xi is palmitoyl, a transporter peptide sequence
  • HIV-TAT peptide sequence Drosophila Antennapedia peptide sequence
  • a steroid or terpenoid lipid X 2 is cysteine, serine, homoalanine; or Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S- glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are independently any nonpolar amino acid
  • X 6 is either absent or at least one nonpolar amino acid (e.g., X 6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl) for use in medical therapy.
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the medical therapy is the treatment of cancer, while in another embodiment, the medical therapy is the treatment of a viral infection.
  • Another embodiment provides for the use of a compound of formula (I):
  • Myristoyl-Cys-Xi-X 2 -X 3 -X 4 -Tyr-(Z)His-OMe (I) to prepare a medicament for inhibiting a viral infection, provided the viral infection is not a HIV or herpes simplex virus-1 (HSV-I) infection, wherein Xi-X 3 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X 4 is either absent or at least one nonpolar amino acid (e,g., X 4 comprises, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and wherein (Z) is (1 ,3 dimethyl) or (3 methyl
  • Xi is alanine
  • X 2 is valine and X 3 is alanine.
  • X 4 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or Sindbis virus infection.
  • the viral infection is an EBV infection.
  • Xi- X 2 -X 3 -X 4 -X 5 -X 6 -Tyr-(Z)His-OMe VII
  • Xi is palmitoyl, a transporter peptide sequence
  • HIV-TAT peptide sequence HIV-TAT peptide sequence
  • Drosophila Antennapedia peptide sequence a steroid or terpenoid lipid
  • X 2 is cysteine, serine, homoalanine
  • Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S- glyceryl-cysteine (Pam 3-cysteine)
  • X 3 -X 5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or is
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1,3 dimethyl).
  • the viral infection is a is HIV, herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza- 3, coxsackie B3, Sindbis virus, or EBV infection.
  • One embodiment provides for the use of a compound of formula (VII): Xi-X 2 - X 3 -X 4 -X 5 -X 6 -TVr-(Z)HiS-OMe (VII), wherein Xi is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid, or a terpenoid lipid; X 2 is cysteine, serine, homoalanine; or X
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
  • the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal.
  • XpX 2 - X 3 -X 4 -X 5 -X 6 -Tyr-(Z)His-OMe VII
  • Xi is palmitoyl, a transporter peptide sequence
  • HIV-TAT peptide sequence Drosophila Antennapedia peptide sequence
  • a steroid or terpenoid lipid X 2 is cysteine, serine, homoalanine; or Xi and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S- glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isole
  • X 3 is alanine
  • X 4 is valine
  • X 5 is alanine
  • X 6 is absent.
  • (Z) is (3 methyl).
  • (Z) is (1 ,3 dimethyl).
  • the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma.
  • the non-Hodgkin's lymphoma is Burkitt's lymphoma.
  • Figure 1 depicts a bar graph of anti-cancer data obtained with Myristoyl-Cys- Ala-Val-Ala-Tyr-(3 methyl)His-OMe.
  • Halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, aralkyl, alkylaryl, etc. denote both straight and branched alkyl groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
  • Aryl includes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (Ci-C 4 )alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • the compounds of the invention may have more than one chiral center and may be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, or enzymatic techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity using the tests described herein, or using other similar tests which are well known in the art.
  • (Ci-C 8 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, hexyl, heptyl or octyl.
  • cycloalkyl encompasses bicycloalkyl (norbornyl, 2.2.2-bicyclooctyl, etc.) and tricycloalkyl (adamantyl, etc.), optionally comprising 1 -2 N, O or S. Cycloalkyl also encompasses (cycloalkyl)alkyl.
  • (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • (C t -C 8 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (C 2 -C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl;
  • (C 2 -C 6 )alkynyl can be ethyny
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl denotes a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1 , 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (Ci-C 8 )alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • heterocycle generally represents a non aromatic heterocyclic group, having from 3 to about 10 ring atoms, which can be saturated or partially unsaturated, containing at least one heteroatom (e.g., 1 , 2, or 3) selected from the group consisting of oxygen, nitrogen, and sulfur.
  • heterocycle groups include monocyclic, bicyclic, or tricyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • heterocycle groups include 1 ,3-dioxolane, 1 ,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuelidine, thiomorpholine, and the like.
  • alkylene refers to a divalent straight or branched hydrocarbon chain (e.g. ethylene -CH 2 CH 2 -).
  • aryl(Ci-C 8 )alkylene for example includes benzyl, phenethyl, 3- phenylpropyl, naphthylmethyl and the like.
  • protecting group refers to any group that, when bound to a hydroxyl, nitrogen, or other heteroatom prevents undesired reactions from occurring at this group and that can be removed by conventional chemical or enzymatic steps to reestablish the 'unprotected' hydroxyl, nitrogen, or other heteroatom group.
  • the particular removable group employed is often interchangeable with other groups in various synthetic routes.
  • Certain removable protecting groups include conventional substituents such as, for example, methyl, allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, methyl methoxy, silyl ethers (e.g., trimethylsilyl (TMS), /-butyl-diphenylsilyl (TBDPS), or /-butyldimethylsilyl (TBS)) and other groups that can be introduced chemically onto a hydroxyl functionality, prevent certain undesirable activity, and later can be selectively removed, either by chemical or enzymatic methods, in conditions that are compatible with the nature of the product.
  • silyl ethers e.g., trimethylsilyl (TMS), /-butyl-diphenylsilyl (TBDPS), or /-butyldimethylsilyl (TBS)
  • TMS trimethylsilyl
  • TDPS /-butyl-
  • Typical carboxy protecting groups described in Greene include benzyl ethers, silyl ethers, esters including sulfonic acid esters, carbonates, sulfates, and sulfonates.
  • suitable carboxy protecting groups include methyl ethers; substituted methyl ethers; substituted ethyl ethers; /?-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl; substituted benzyl ethers (p-methoxybenzyl, 3,4-dimethoxybenzyl, ⁇ -nitrobenzyl, /?-nitrobenzyl, /?-halobenzyl, 2,6-dichlorobenzyl, /7-cyanobenzyl,/>-phenylbenzyl, 2- and 4-picolyl, diphenylmethyl, 5-dibenzosuberyl, triphenylmethyl,/7-methoxyphenyl-diphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, l ,3-benzodithiolan-2-yl, benzisothiazoly
  • amino acid includes and naturally occurring or synthetic amino acid including D or L amino acids, including but not limited to polar amino acids (Asp, GIu, Tyr, Asn, GIn, Thr, Ser, Cys, Lys, Arg, His) and non-polar amino acids (Trp, GIy, Ala, Phe, Pro, Met, VaI, Leu, He).
  • polar amino acids Asp, GIu, Tyr, Asn, GIn, Thr, Ser, Cys, Lys, Arg, His
  • Trp GIy, Ala, Phe, Pro, Met, VaI, Leu, He.
  • sample refers to any bodily fluid, cell(s) (eukaryotic and/or prokaryotic), tissue(s) or animal(s), including mammals, preferably humans, or plant to which the present invention may be applied.
  • cell(s) eukaryotic and/or prokaryotic
  • tissue(s) or animal(s) including mammals, preferably humans, or plant to which the present invention may be applied.
  • treat or “treating” includes treating, preventing, ameliorating, or inhibiting a disease, disorder and/or a symptom of a disease and/or a disorder of an organism.
  • an "effective amount” generally means a sufficient amount of a compound to provide the desired local or systemic effect and performance.
  • pharmaceutically acceptable carrier refers to carrier materials without significant pharmacological activity at the quantities used that are suitable for administration with other compounds, and include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluents, solubilizer, microspheres, liposomes, microparticles, lipid complexes, or the like, that is sufficiently nontoxic at the quantities employed and does not interact with the drug to be administered in a deleterious manner.
  • Suitable carriers for use herein include water, buffers, mineral oil, silicone, inorganic or organic gels, aqueous emulsions, liquid sugars, lipids, microparticles, waxes, petroleum jelly, and a variety of other oils and polymeric materials.
  • tumor cells refers to an aggregate of abnormal cells and/or tissue which may be associated with diseased states that are characterized by uncontrolled cell proliferation.
  • the disease states may involve a variety of cell types, including, for example, endothelial, epithelial and myocardial cells. Included among the disease states are neoplasms, cancer, and leukemia.
  • any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is Ci-C 4 alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X is independently selected from H or a C]-C 4 alkyl group).
  • salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • COMPOUNDS OF THE INVENTION AND VARIANTS THEREOF One embodiment provides a compound of formula (XX):
  • X 1 is C ⁇ -C ⁇ alkylcarbonyl
  • X 2 is any amino acid or absent or
  • X 1 and X 2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
  • X 3 -X 5 are any amino acid, such as a nonpolar amino acid, or absent;
  • X 6 is absent or at least one amino acid, such as a nonpolar amino acid
  • R is independently at each occurrence H or (Ci-C 6 )alkyl
  • R 1 and R 2 are independently (Ci-C 4 )alkyl or R 1 and R 2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO 2 Y, CONYY 1 , NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O) 2 , wherein Y and Y' independently at each occurrence comprises H, or (Ci-C 6 )alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with
  • R 3 is any carboxy protecting group
  • R 4 and R 5 are each independently H, halo, cyano, nitro, C(O)R 6 , (Ci-Cio)alkyl, (C 2 -C,o)alkenyl, (C 2 -C , 0 )alkynyl, (C,-C, 0 )haloalkyl, (C 3 -C, 0 )cycloalkyl, (C 3 - Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C 6 )alkyl, OR, halo, NR 2 , cyano, nitro, (C,-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, carboxamid
  • C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C
  • X 1 is myristoyl or palmitoyl. In another embodiment, X 2 is cysteine.
  • R 1 and R 2 are methyl; or one of R 1 and R 2 is methyl and the other is H.
  • R 3 is OMe.
  • X 2 -X 6 can be absent or any number of O, S, CR, NR or any substituted or unsubstituted amino acid.
  • X 3 is not Ala. In another embodiment, X 4 is not VaI. In another embodiment, X 5 is not Ala. In one embodiment, X 3 is not Ala, X 4 is not VaI and X 5 is not Ala.
  • a compound of formula (XX) may have the following structure and characteristics:
  • the compound may have the following structure and characteristics: (N-terminal end) (C-terminal end)
  • This chemical structure is a natural product isolated and purified from Heliothis virescens insect hemolymph (blood) that has essentially none or very low cytotoxicity against human foreskin fibroblast cells.
  • a natural product is designed by nature to kill something else and not the host cell itself. This is an important characteristic of the compound if used as a medicinal drug. A compound cannot be too cytotoxic to host cells if it is to be used as a beneficial drug to treat disease.
  • the N-terminal end of the compound of formula (I) is lipophilic and it is believed that its general function is to get the compound across and through the cell membrane.
  • the positively charged C-terminal end, with its ring-shaped structure, which contains a histidine with two methyl groups (L-histidine, 1 ,3-dimethyl, methyl ester (not before found in nature)) is believed to inhibit DNA synthesis.
  • the imidazole ring of the histidine can have anti-helminthic, anti-fungal, anti-viral, anti-microbial, antibacterial, anti-protozoan, and/or insecticidal activity.
  • Epstein-Barr Virus EBV
  • human immunodeficiency virus HIV
  • VSV vesicular stomatitis virus
  • parainfluenxa-3 coxsackie B3 and Sindbus virus.
  • Epstein-Barr Virus is described as a cancer-promoting double-stranded DNA virus (Thompson, M. P., Kurzrock, R. Clin. Cancer Res. 10, 803-821 , 2004).
  • Antiviral drugs are purine analogues and have ring-shaped purine structures as their active sites which inhibit DNA synthesis.
  • the nitrogen-containing purine base has a double-ringed structure.
  • the anti-tumor and antiviral compounds of the instant invention have at least one purine-like ring along with other rings at its C-terminal end.
  • the compound contains six methyl groups (- CH 3 ); however, this is not an absolute number and the compounds may be generated with more or fewer methyl groups (e.g., 1 , 2, 3, 4, 5, 7, 8, 9, 10 etc).
  • methyl groups are needed for rigidity of a compound and for good biological activity. Further, it is believed that methyl groups increase metabolic life, but also decrease the absorbance of a compound through the cell membrane.
  • Modification of the N-terminal end of the instant compound can enhance passage of the compound across and through the cell membrane in order to increase its concentration in the cell, and thus, effectiveness and biological activity inside the cell. ...
  • the compound can be altered in order to target a specific cell type.
  • acute myeloid leukemia is the most common adult leukemia and is also a childhood leukemia.
  • Acute myeloid leukemia affects various white blood cells including granulocytes (70% of which are neutrophils), '" " monocytes and platelets.
  • Neutrophils and monocytes both express Toll-like receptor 2.
  • Pam 2-cysteine and Pam 3-cysteine are lipid moieties that can specifically bind to Toll- like receptor 2.
  • the anti-tumor compounds described herein are linked to Pam 2- cysteine or Pam 3-cysteine at the N-terminal end, then the anti-tumor compounds are specifically targeted for entry into leukemic tumor cells.
  • This mechanism of action can also be effective for acute myeloid leukemia when myristic acid is replaced by palmitic acid at the N-terminal end as is described below.
  • This treatment approach can further be applicable for treatment of chronic myeloid leukemia.
  • the anti-tumor compound described herein was very effective in vitro against all five of the five different leukemia cell tissue cultures tested by the National Cancer Institute (discussed in detail below). Example of N-terminal modification are presented below.
  • any agent that aids in cell targeting and entry of the compounds can be used in the compounds, compositions and method of the instant invention.
  • the compounds of the invention can be synthesized to incorporate a cell targeting agent (e.g., any material or substance which may promote targeting of tissues, cells and/or receptors in vivo and/or in vitro of the compounds/compositions of the present invention), which can include, but is not limited to, peptides or proteins such as antibodies, including monoclonal and polyclonal (e.g., anti-CD20 antibody, anti-IL-2R ⁇ antibody) and fragments thereof, ligands, including receptor ligands/proteins (preferably those that specifically bind to their receptors), peptides, polypeptides (e.g., Type I interferon, Type II interferon), cytokines (e.g., interleukin-1 ("IL-I "), interleukin-2 ("IL-2”), interleukin-3 (“IL-3”), interleukin-4 ("IL-I "), inter
  • Myristoyl (Ci 4 fatty acid) can be replaced with palmitoyl (Ci 6 fatty acid).
  • the - SH group of cysteine can be active in forming disulfide bond dimers of the compound.
  • the dimer form of the compound can enhance its movement across the cell membrane and also increase its biological activity.
  • Myristoyl is a C) 4 fatty acid found in insect cell membranes, not in mammalian cell membranes.
  • Palmitoyl is a C) 6 fatty acid found in mammalian cell membranes. Substituting palmitoyl for myristoyl will make the fatty acid two carbons longer and can facilitate transfer of the compound across and through the mammalian cell membrane. This will increase concentration of the compound inside the cell, thus increasing cytoplasmic and nuclear effectiveness of the drug.
  • N-terminal end (C-terminal end)
  • Myristoyl (Ci 4 fatty acid) can be replaced with palmitoyl (Ci 6 fatty acid).
  • Block the -SH group of cysteine by, for example, methylation (adding -CH 3 group) so that dimerization of the compound with a disulfide bond (-S-S-) does not occur (chemical protecting/blocking groups and strategies for protection/deprotection are well known in the art. See e.g.. Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991).
  • Myristoyl (Ci 4 fatty acid) can be replaced with palmitoyl (Ci 6 fatty acid). Then synthesize as a dimer with a disulfide bond and use the oxidized product. Two palmitic acids would then be present and this can enhance even more passage of the compound across the cell membrane along with its having two C-terminal ends for increased biological activity.
  • Palmitoyl-Cys-Ala-Val-Ala-Tyr-(1,3 dimethyl)His-OMe (Synthesize as a Dimer) (IV).
  • Molecular Weight 1886.5 (Dimer)
  • N-terminal end to increase transport of the compound across the cell membrane and/or target the compounds to a selected cell type, include, but are not limited to: replace myristic acid at N-terminal end with a Transporter Peptide Sequence (these are short basic peptide sequences that promote translocation across cell membranes, perhaps by endocytosis; examples are as follows: Console, S. et al., Antennapedia and HIV-Transactivator of Transcription (TAT) 'protein transduction domains' promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans. J. Biol. Chem.
  • TAT HIV-Transactivator of Transcription
  • N-Terminal end to prevent dimerization of the compound include, but are not limited to: use an amino acid that has similar characteristics as the amino acid it is replacing. For example, replace cysteine with serine, which has the same electrophilic properties (O vs. S) as cysteine or replace cysteine with homoalanine (ABU), which has the same chain length as cysteine.
  • Other amino acid substitutions, including conservative amino acid substitutions, throughout the molecule are also encompassed by the instant invention.
  • the middle amino acid sequence Ala-Val-Ala of the compound can be substituted with non- polar amino acids or lengthened with non-polar amino acids.
  • compositions of the invention are screened for inhibitory activity against viruses by any of the conventional techniques for evaluating such activity (e.g., in vitro formazan assay for HlV-I anti-viral activity).
  • typically compositions are first screened for inhibition of infection in vitro and compositions showing inhibitory activity are then screened for activity in vivo.
  • X 10 ⁇ 7 M and preferably less than about 5 X 10" ⁇ M are preferred for in vivo use.
  • compositions of the invention are screened for activity against cancer by any of the conventional techniques for evaluating enzyme activity.
  • typically compositions are first screened for activity against cancer in vitro and compositions showing activity are then screened for activity in vivo.
  • Useful in vitro screens have been described in detail and will not be elaborated here. However, the examples describe suitable in vitro assays.
  • the in vitro assays used to determine anti-Epstein-Barr Virus (EBV) activity and anti-cancer activity inhibit DNA synthesis/replication, cell growth and cell division.
  • the compound of interest inhibited DNA synthesis/replication of EBV in Akata cells (B-lymphocytes) in in vitro tissue culture.
  • the effect of the compound on cancer cell growth was growth inhibition (inhibition of cell division occurring during the cell growth cycle) of cancer cells in in vitro tissue culture.
  • viruses by the compounds of the invention include, but are not limited to, Abelson leukemia virus, Abelson murine leukemia virus, Abelson's virus, acute laryngotracheobronchitis virus, Sydney River virus, adeno associated virus group, Adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, Aleutian mink disease parvovirus, alfalfa mosaic virus, alpharetrovirus, Alphavirus, ALV related virus, Amapari virus, Andean potato mottle virus, Aphthovirus, Aquareovirus, arbovirus, arbovirus C, arbovirus group A, arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus, Argentinean hemorrhagic fever virus, Arterivirus, Astrovirus, Ateline herpesvirus group, Aujezky's disease virus, Aura virus
  • Closterovirus Cocal virus, Coho salmon reovirus, coital exanthema virus, Colorado tick fever virus, Coltivirus, Columbia SK virus, Commelina yellow mottle virus, common cold virus, Comovirus, congenital cytomegalovirus, contagious ecthyma virus, contagious pustular dermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpea chlorotic mottle virus, cowpea mosaic virus, cowpea virus, cowpox virus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus), cricket paralysis virus, Crimean-Congo hemorrhagic fever virus, croup associated virus, Crypotovirus, Cucumovirus, Cypovirus, cytomegalovirus, cytomegalovirus group, cytoplasmic polyhedrosis virus, deer papillomavirus, defective virus, deltaretrovirus, Dengue, Densovirus, Dependovirus, Dhori virus, Dian
  • Mokola virus Molluscipoxvirus, Molluscum contagiosum virus, monkey B virus, monkeypox virus, Mononegavirales, Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus, mouse K virus, mouse leukemia virus, mouse mammary tumor virus, mouse minute virus, mouse pneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosal disease virus, mumps virus, murid betaherpesvirus 1 , murid cytomegalovirus 2, murine cytomegalovirus group, murine encephalomyelitis virus, murine hepatitis virus, murine leukemia virus, murine, nodule inducing virus, murine polyomavirus, murine sarcoma virus, Muromegalovirus, Murray Valley encephalitis virus, myxom
  • Retrovirus Rhabdovirus, Rhabdovirus carpia, Rhadinovirus, rhinovirus, Rhizidiovirus, rice dwarf virus, rice gall dwarf virus, rice hoja blanca virus, rice ragged stunt virus, Rift Valley fever virus, Riley's virus, rinderpest virus, RNA tumor virus, RNA virus, Ross River virus, Rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeola virus, Rubivirus, Russian autumn encephalitis virus, S6- 14-03 virus, SA 1 1 simian virus, SA 15, SA2 virus, SA6 virus, SA8 virus, Sabia virus, Sabio virus, Saboya virus, Sabulodes caberata GV, Sacbrood virus, Saccharomyces cerevisiae virus L-A, Saccharomyces cerevisiae virus La, Saccharomyces cerevisiae virus LBC, Sagiyama virus, Saguaro cactus virus, Saimierine herpesvirus 1
  • Sulfolobus virus 1 Sunday Canyon virus, Sunflower crinkle virus, Sunflower mosaic virus, Sunflower rugose mosaic virus, Sunflower yellow blotch virus, Sunflower yellow ringspot virus, Sun-hemp mosaic virus, swamp fever virus, Sweet clover necrotic mosaic virus, Sweet potato A virus, Sweet potato chlorotic leafspot virus, Sweet potato feathery mottle virus, Sweet potato internal cork virus, Sweet potato latent virus, Sweet potato mild mottle virus, Sweet potato russet crack virus, Sweet potato vein mosaic virus, Sweet potato yellow dwarf virus, Sweetwater Branch virus, Swine cytomegalovirus, Swine infertility and respiratory syndrome virus, swinepox virus, Swiss mouse leukemia virus, Sword bean distortion mosaic virus, Synaxis jubararia NPV, Synaxis pallulata NPV, Synetaeris tenuifemur virus, Syngrapha selecta NPV, T4 phage, T7 phage, TAC virus, Tacaiuma virus, Tacaribe complex virus, Tacari
  • Thermoproteus virus 4 Thiafora virus, Thimiri virus, Thistle mottle virus, Thogoto virus, Thormodseyjarklettur virus, Thosea asigna virus, Thosea baibarana NPV, Thosea sinensis GV, Thottapalayam virus, Thylidolpteryx ephemeraeformis NPV, Thymelicus lineola NPV, Tibrogargan virus, Ticera castanea NPV, Tick borne encephalitis virus, Tillamook virus, Tilligerry virus, Timbo virus, Tilmboteua virus, Tilmaroo virus, Tindholmur virus, Tinea pellionella NPV, Tineola hisselliella NPV, Tinpula paludosa NPV, Tinracola plagiata NPV, Tioman virus, Tlacotalpan virus, Tobacco bushy top virus, Tobacco etch virus, Tob
  • Virus transforming virus, Tree shrew adenovirus 1 , tree shrew herpesvirus, Triatoma virus, Tribec virus, Trichiocampus irregularis NPV, Trichiocampus viminalis NPV, Trichomonas vaginalis virus, Trichoplusia ni cypovirus 5, Trichoplusia ni granulovirus, Trichoplusia ni MNPV, Trichoplusia ni Single SNPV, Trichoplusia ni virus,
  • Trichosanthes mottle virus Triticum aestivum chlorotic spot virus, Trivittatus virus, Trombetas virus, Tropaeolum virus 1 , Uasin Gishu disease virus, Kenya S virus, Ugymyia sericariae NPV, ulcerative disease rhabdovirus, Ullucus mild mottle virus, Ullucus mosaic virus, Ullucus virus C, Umatilla virus, Umbre virus, Una virus, Upolu virus, UR2 sarcoma virus, Uranotaenia sapphirina NPV, Urbanus proteus NPV, Urucuri virus, Ustilago maydis virus 1 , Ustilago maydis virus 4, Ustilago maydis virus 6, Usutu virus, Utinga virus, Utive virus, Uukuniemi virus group, vaccinia virus, Vaeroy virus, Vallota mosaic virus, salsa atalanta NPV, salsa NPV, salsa, Alfapox virus, Tri
  • treatment of viruses/viral infections by the compounds of the invention include, but are not limited to, HIV, herpes simplex virus-1 (HSV-I), herpes simplex virus-2 (HSV-2), vesicular stomatitis, parainfluenza-3, coxsackie B3, Sindbis viruses and Epstein Barr viruses (EBV).
  • HIV herpes simplex virus-1
  • HSV-2 herpes simplex virus-2
  • vesicular stomatitis vesicular stomatitis
  • parainfluenza-3 parainfluenza-3
  • coxsackie B3 coxsackie B3, Sindbis viruses
  • Epstein Barr viruses Epstein Barr viruses
  • the treatment of viruses/viral infections does not include HIV or herpes simplex virus-1 (HSV-I).
  • the treatment of viruses/viral infections does not include HIV, herpes simplex virus-1 (HSV-I), herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenzal, coxsackie B3, or Sindbis viruses.
  • the treatment of viruses/viral infections includes Epstein Ban- virus (EBV).
  • Epstein-Barr virus also called Human herpesvirus 4 (HHV-4)
  • HHV-4 Human herpesvirus 4
  • EBV Epstein-Barr virus
  • the EBV linear virus genome circularizes and the virus subsequently persists within the cell as an episome.
  • the virus can execute several distinct programs of gene expression which can be broadly categorized as being the lytic cycle or latent cycle.
  • the lytic cycle or productive infection results in staged expression of a host of viral proteins with the ultimate objective of producing infectious virions. This phase of infection usually does not inevitably lead to lysis of the host cell as EBV virions are produced by budding from the infected cell.
  • the latent cycle (lysogenic) programs are those that do not result in production of virions.
  • a very limited, distinct set of viral proteins are produced during the latent cycle infection. These include Epstein-Barr nuclear antigen (EBNA)-I, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-leader protein (EBNA-LP) and latent membrane proteins (LMP)- 1 , LMP-2A and LMP-2B and the Epstein-Barr encoded RNAs (EBERs).
  • EBNA Epstein-Barr nuclear antigen
  • EBNA-2 Epstein-Barr nuclear antigen
  • EBNA-3A EBNA-3B
  • EBNA-3C EBNA-leader protein
  • LMP latent membrane proteins
  • LMP-2A and LMP-2B the Epstein-Barr encoded RNAs
  • EBERs Epstein-Barr encoded RNAs
  • lymphoblastoid cell lines eventually emerge that are capable of indefinite growth.
  • the growth transformation of these cell lines is the consequence of viral protein expression.
  • EBNA-2, EBNA-3C and LMP-I are believed to be needed for transformation, while EBNA-LP and the EBERs are not.
  • the EBNA-I protein is generally believed to be needed for maintenance of the virus genome (Yates JL, et al. (1985) Nature 313: 812-5).
  • the virus executes some or all of its repertoire of gene expression programs to establish a persistent infection. Given the initial a " bsence of host immunity, the lytic cycle produces large amounts of virus to infect other (presumably) B-lymphocytes within the host.
  • the latent programs reprogram and subvert infected B-lymphocytes to proliferate and bring infected cells to the sites at which the virus presumably persists.
  • the virus persists by turning off most (or possibly all) of its genes, only occasionally reactivating to produce fresh virions.
  • a balance is eventually struck between occasional viral reactivation and host immune surveillance removing cells that activate viral gene expression.
  • the site of persistence of EBV may be bone marrow.
  • EBV-positive patients who have had their own bone marrow replaced with bone marrow from an EBV-negative donor are found to be EBV-negative after transplantation (Gratama JW, et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85: 8693-6).
  • EBV nuclear proteins are produced by alternative splicing of a transcript starting at either the Cp or Wp promoters at the left end of the genome (in the conventional nomenclature).
  • the genes are ordered EBNA-LP/EBNA-2/EBNA- 3A/EBNA-3B/EBNA-3C/EBNA-1 within the genome.
  • EBV microRNAs are encoded by two transcripts, one set in the BART gene and one set near the BHRFl cluster.
  • the three BHRFl miRNAS are expressed during type III latency while the large cluster of BART miRNAs (up to 20 miRNAs) are expressed during type II latency.
  • the functions of these miRNAs are currently unknown.
  • Epstein-Barr can cause infectious mononucleosis, also known as "glandular fever,” “Mono” and "Pfeiffer's disease.” Infectious mononucleosis is caused when a person is first exposed to the virus, generally during or after adolescence.
  • EBV is also associated with various malignancies. The strongest evidence linking EBV and cancer formation is found in Burkitt's lymphoma and nasopharyngeal carcinoma. Burkitt's lymphoma is a type of Non-Hodgkin's lymphoma. Burkitt's lymphoma is common in equatorial Africa and is co-existent with the presence of malaria. Malaria infection causes reduced immune surveillance of EBV immortalized B cells, thus allowing their proliferation. This proliferation increases the chance of a mutation to occur. Repeated mutations can lead to the B cells escaping the body's cell- cycle control, thus allowing the cells to proliferate unchecked, resulting in the formation of Burkitt's lymphoma.
  • Burkitt's lymphoma commonly affects the jaw bone, forming a huge tumor mass. It responds to chemotherapy treatment, namely cyclophosphamide, but recurrence is common. Other B cell lymphomas arise due to EBV in immuno-compromised patients such as those with AIDS or who have undergone organ transplantation with associated immunosuppression (Post-Transplant Lymphoproliferative Disorder (PTLPD)). Smooth muscle tumors are also associated with the virus in malignant patients.
  • PTLPD Post-Transplant Lymphoproliferative Disorder
  • Nasopharyngeal carcinoma is a cancer found in the upper respiratory tract, most commonly in the nasopharynx, and is linked to the EBV virus. It is found predominantly in Southern China and Africa, due to both genetic and environmental factors. It is much more common in people of Chinese ancestry (genetic), but is also linked to the Chinese diet of a high amount of smoked fish, which contain nitrosamines, well known carcinogens (environmental).
  • EBV has been postulated to be a trigger for a subset of chronic fatigue syndrome patients (Lerner AM, et al., (2004) In Vivo 18(2): 101 -6) as well as multiple sclerosis and other autoimmune diseases (L ⁇ nemann JD, and M ⁇ nz C (2007) Current neurology and neuroscience reports 7(3): 253-8).
  • Non-Hodgkin's lymphomas including primary cerebral lymphoma and Burkitt's lymphoma; lymphomas of immunosuppressed subjects (e.g., AIDS patients or transplant recipients); B-cell tumors, T-cell tumors; B lymphoproliferative disease; Hodgkin's lymphoma/disease; nasopharyngeal carcinoma; post-transplant lymphoproliferative disorder; herpangina; multiple sclerosis; Hairy leukoplakia; Common variable immunodeficiency (CVID) and Kikuchi's disease.
  • No anti-viral therapies are currently in use with regards to treatment of these diseases/disorders. Currently, such patients are treated by only supportive treatment regimes.
  • CANCERS SOLID AND NON-SOLID
  • the compounds, compositions and methods of this invention are also useful in the treatment of a variety of cancers (solid and non-solid) and tumors including, but not limited to tumors of the breast, bladder, cervix, colon, gall bladder, kidney, liver, lung, pancreas, ovary, prostate, skin, stomach, thyroid, and the like.
  • compositions of the invention can be used to inhibit, treat or prevent carcinomas such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; blood, hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomy
  • the invention can be used to inhibit, treat or prevent Non-Small Cell Lung Cancer, Colon Cancer, Breast Cancer, Ovarian Cancer, Leukemia, Renal Cancer, Melanoma, and/or CNS (Brain) Cancer.
  • EXEMPLARY METHODS OF MAKING/ISOLATING THE COMPOUNDS OF THE INVENTION The invention also relates to methods of making and/or isolating the compounds/compositions of the invention.
  • the compounds are prepared by any of the applicable techniques of organic synthesis available to the art. Many such techniques are well known in the art and are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1 , Ian T. Harrison and Shuyen Harrison, 1971 ; Vol.
  • the cited reference material contains detailed descriptions of such conditions.
  • temperatures will be -100°C to 200°C
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 0 C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 °C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 °C to -100 0 C) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • the compound of formula (I) can be isolated from the hemolymph of Heliothis virescens, as discussed in D. Ourth, Antiviral activity against human immunodeficiency virus- 1 in vitro by myristoylated-peptide from Heliothis virescens, Biochemical and Biophysical Research Communications, 320, 190-196, 2004. Briefly, the hemolymph (blood) was collected with capillary tubes from fifth-instar larvae under ice-chilling conditions. Cell-free hemolymph was obtained by centrifugation at 10,000 rpm for 10 min at 4°C. The hemolymph was stored at -80°C.
  • the hemolymph was thawed at room temperature and then centrifuged at 10,000 rpm for 10 min at 4°C to separate the melanin precipitate.
  • the melanin precipitate after washing once with sterile water, was solubilized in 0.05 M phosphate buffered saline, pH 7.55, with vortexing. Following centrifugation, the supernatant was applied to a gel-filtration HPLC-column (described below).
  • Solubilized products of the insect melanization reaction were analyzed by high pressure liquid chromatography (HPLC) (ISCO Instrumentation, Lincoln, NE) to isolate and purify the hemolymph antiviral factor. Three major peaks and four minor peaks were seen when the solubilized melanin was applied to a low molecular weight Shodex KW- 802.5 gel-filtration (separation range 100-50,000 Da) HPLC column (Millipore, Milford, MA) in 0.2 sodium phosphate buffer, pH 7.0. One milliliter tube fractions of these peaks were collected. Three of the low molecular weight fractions (#12, #15, and #16) showed major anti-HIV-1 activity using the formazan assay. One of the three tube fractions (#16) showed greater antiviral activity against HIV-I and was further purified and separated by reverse-phase HPLC (C- 18 column, Rainin Instrument, Woburn, MA).
  • HPLC high pressure liquid chromatography
  • Elution of antiviral retention fractions by C- 18 reverse-phase HPLC was performed with a linear gradient of 0-50% acetonitrile in 0.1% trifluoroacetic acid (TFA) over a period of 50 min at a flow rate of 1 ml/min.
  • TFA trifluoroacetic acid
  • the organic solvent acetonitrile/water (50/50 v/v) containing 0.1% TFA was used as the final concentration of eluant.
  • Ultraviolet absorption was monitored at 280 nm.
  • the eluted retention fractions were vacuum concentrated (Speed Vac, Savant, Farmingdale, NY) and then dissolved in 0.05 M phosphate buffered saline, pH 7.2.
  • the formazan assay for anti-HIV activity was done on the purified retention fractions obtained by C-18 reverse-phase HPLC.
  • MALDI-TOF and MALDl-CID mass spectrometry
  • the compound is composed of 6 amino acids with a fatty acid at the N-terminal end of the molecule.
  • the C-terminal end of the molecule contains an amino acid never before found in nature that gives the molecule a permanent positive charge at this end.
  • the compound has broad- spectrum anti-viral activity against DNA and RNA viruses and cancer cells.
  • the compounds of the invention can be prepared recombinantly, for example, the synthetic gene or cloned gene, or a variant thereof, coding for a compound of the instant invention can be expressed (e.g., over-expressed) in a cell, such as an insect cell or other eukaryotic or prokaryotic cell with appropriate machinery to produce such a compound.
  • a cell such as an insect cell or other eukaryotic or prokaryotic cell with appropriate machinery to produce such a compound.
  • Isolation and preparation of expression cassettes and vectors can be readily prepared by an art worker with routine techniques available to the art worker in the biotechnology field.
  • compositions comprising the compounds of the invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).
  • the compounds of the invention and/or combinations with other agents may be administered as single or divided dosages.
  • the compounds of the invention can be administered in dosages of at least about 0.01 mg/kg to about 500 to 750 mg/kg, of at least about 0.01 mg/kg to about 300 to 500 mg/kg, at least about 0.1 mg/kg to about 100 to 300 mg/kg or at least about 1 mg/kg to about 50 to 100 mg/kg of body weight, although other dosages may provide beneficial results.
  • the amount administered will vary depending on various factors including, but not limited to, the compound chosen, the disease, the weight, the physical condition, the health, the age of the subject, whether prevention or treatment is to be achieved, and if the compound is chemically modified.
  • Administration of the therapeutic agents (compounds of the invention) in accordance with the present invention may be in a single dose, in multiple doses, in a continuous or intermittent manner, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
  • the administration of the compounds of the invention and/or other agents of the invention may be essentially continuous over a preselected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated.
  • compositions of the invention are synthesized, isolated or otherwise obtained, purified as necessary or desired and then lyophilized and stabilized as necessary or desired.
  • the compounds of the invention can then be adjusted to the appropriate concentration, and optionally combined with other agents.
  • the absolute weight of a given compound included in a unit dose can vary widely. For example, about 0.01 to about 2 g, or about 0.1 to about 500 mg, of at least one compound of the invention, or a plurality of compounds can be administered.
  • the unit dosage can vary from about 0.01 g to about 50 g, from about 0.01 g to about 35 g, from about 0.1 g to about 25 g, from about 0.5 g to about 12 g, from about 0.5 g to about 8 g, from about 0.5 g to about 4 g, or from about 0.5 g to about 2 g.
  • Daily doses of the compounds of the invention can vary as well.
  • Such daily doses can range, for example, from about 0.1 g/day to about 50 g/day, from about 0.1 g/day to about 25 g/day, from about 0.1 g/day to about 12 g/day, from about 0.5 g/day to about 8 g/day, from about 0.5 g/day to about 4 g/day, and from about 0.5 g/day to about 2 g/day.
  • one or more suitable unit dosage forms comprising the therapeutic compounds of the invention can be administered by a variety of routes including oral, parenteral (including subcutaneous, intravenous, intramuscular and intraperitoneal), rectal, dermal, transdermal, intrathoracic, intrapulmonary and intranasal (respiratory) routes.
  • the compounds of the invention are administered locally to tumor or cancer sites.
  • the therapeutic agents may also be formulated for sustained release (for example, using microencapsulation, see WO94/07529, and U.S. Patent No.4,962,091).
  • the formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods available to the pharmaceutical arts. Such methods may include the step of mixing the therapeutic agents with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system.
  • the therapeutic agents of the invention are prepared for oral administration, they are generally combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form.
  • a pharmaceutically acceptable carrier diluent or excipient
  • the therapeutic agents may be present as a powder, a granular formulation, a solution, a suspension, an emulsion or in a natural or synthetic polymer or resin for ingestion of the active ingredients from a chewing gum.
  • the therapeutic agents may also be presented as a bolus, electuary or paste.
  • Orally administered therapeutic agents of the invention can also be formulated for sustained release, e.g., the therapeutic agents can be coated, micro-encapsulated, or otherwise placed within a sustained delivery device.
  • the total active ingredients in such formulations comprise from 0.001 to 99.9% by weight of the formulation.
  • pharmaceutically acceptable means a carrier, diluent, excipient, and/or salt that is compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • compositions containing the therapeutic agents of the invention can be prepared by procedures available to the art using well-known and readily available ingredients.
  • the therapeutic agents can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, solutions, suspensions, powders, aerosols and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include water, buffers, as well as fillers and extenders such as starch, cellulose, sugars, mannitol, and silicic derivatives.
  • Binding agents can also be included such as carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone.
  • Moisturizing agents can be included such as glycerol, disintegrating agents such as calcium carbonate and sodium bicarbonate.
  • Agents for retarding dissolution can also be included such as paraffin.
  • Resorption accelerators such as quaternary ammonium compounds can also be included.
  • Surface active agents such as cetyl alcohol and glycerol monostearate can be included.
  • Adsorptive carriers such as kaolin and bentonite can be added.
  • Lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols can also be included. Preservatives may also be added.
  • the compositions of the invention can also contain thickening agents such as cellulose and/or cellulose derivatives. They may also contain gums such as xanthan, guar or carbo gum or gum arabic, or alternatively polyethylene glycols, bentones and montmorillonites, and the like.
  • tablets or caplets containing the therapeutic agents of the invention can include buffering agents such as calcium carbonate, magnesium oxide and magnesium carbonate.
  • Caplets and tablets can also include inactive ingredients such as cellulose, pregelatinized starch, silicon dioxide, hydroxy propyl methyl cellulose, magnesium stearate, microcrystalline cellulose, starch, talc, titanium dioxide, benzoic acid, citric acid, corn starch, mineral oil, polypropylene glycol, sodium phosphate, zinc stearate, and the like.
  • Hard or soft gelatin capsules containing at least one therapeutic agent of the invention can contain inactive ingredients such as gelatin, microcrystalline cellulose, sodium lauryl sulfate, starch, talc, and titanium dioxide, and the like, as well as liquid vehicles such as polyethylene glycols (PEGs) and vegetable oil.
  • inactive ingredients such as gelatin, microcrystalline cellulose, sodium lauryl sulfate, starch, talc, and titanium dioxide, and the like
  • liquid vehicles such as polyethylene glycols (PEGs) and vegetable oil.
  • enteric-coated caplets or tablets containing one or more therapeutic agents of the invention are designed to resist disintegration in the stomach and dissolve in the more neutral to alkaline environment of the duodenum.
  • the therapeutic agents of the invention can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous, intraperitoneal or intravenous routes.
  • the pharmaceutical formulations of the therapeutic agents of the invention can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension or salve.
  • the therapeutic agents may be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion containers or in multi-dose containers.
  • preservatives can be added to help maintain the shelve life of the dosage form.
  • the compounds of the invention with optional other ingredients may form suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compounds of the invention with optional other ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • formulations can contain pharmaceutically acceptable carriers, vehicles and adjuvants that are well known in the art. It is possible, for example, to prepare solutions using one or more organic solvent(s) that is/are acceptable from the physiological standpoint, chosen, in addition to water, from solvents such as acetone, ethanol, isopropyl alcohol, glycol ethers such as the products sold under the name "Dowanol,” polyglycols and polyethylene glycols, C] -C4 alkyl esters of short-chain acids, ethyl or isopropyl lactate, fatty acid triglycerides such as the products marketed under the name "Miglyol,” isopropyl myristate, animal, mineral and vegetable oils and polysiloxanes.
  • organic solvent(s) that is/are acceptable from the physiological standpoint, chosen, in addition to water, from solvents such as acetone, ethanol, isopropyl alcohol, glycol ethers such as the products sold under the name "Dowanol,” polyg
  • antioxidants such as t-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene and ⁇ -tocopherol and its derivatives can be added.
  • the compounds of the invention are well suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the therapeutic agents, for example, in a particular part of the intestinal or respiratory tract, possibly over a period of time.
  • Coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide- glycolates, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, envelopes, and protective matrices are useful to coat indwelling devices, e.g., stents, catheters, peritoneal dialysis tubing, draining devices and the like.
  • the therapeutic agents may be formulated as is known in the art for direct application to a target area.
  • Forms chiefly conditioned for topical application take the form, for example, of creams, milks, gels, dispersion or microemulsions, lotions thickened to a greater or lesser extent, impregnated pads, ointments or sticks, aerosol formulations (e.g., sprays or foams), soaps, detergents, lotions or cakes of soap.
  • Other conventional forms for this purpose include wound dressings, coated bandages or other polymer coverings, ointments, creams, lotions, pastes, jellies, sprays, and aerosols.
  • the therapeutic agents of the invention can be delivered via patches or bandages for dermal administration.
  • the compounds of the invention can be formulated to be part of an adhesive polymer, such as polyacrylate or acrylate/vinyl acetate copolymer.
  • an adhesive polymer such as polyacrylate or acrylate/vinyl acetate copolymer.
  • the backing layer can be any appropriate thickness that will provide the desired protective and support functions. A suitable thickness will generally be from about 10 to about 200 microns.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the therapeutic agents can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122; 4,383,529; or 4,051 ,842.
  • the percent by weight of a therapeutic agent of the invention present in a topical formulation will depend on various factors, but generally will be from 0.001 % to 95% of the total weight of the formulation, and typically 0.01 -85% by weight.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Drops such as eye drops or nose drops, may be formulated with one or more of the therapeutic agents in an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents.
  • Liquid sprays are conveniently delivered from pressurized packs. Drops can be delivered via a simple eye dropper-capped bottle, or via a plastic bottle adapted to deliver liquid contents dropwise, via a specially shaped closure.
  • the therapeutic agents may further be formulated for topical administration in the mouth or throat.
  • the active ingredients may be formulated as a lozenge further comprising a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the composition in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the composition of the present invention in a suitable liquid carrier.
  • a flavored base usually sucrose and acacia or tragacanth
  • pastilles comprising the composition in an inert base such as gelatin and glycerin or sucrose and acacia
  • mouthwashes comprising the composition of the present invention in a suitable liquid carrier.
  • the pharmaceutical formulations of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and salts of the type that are available in the art.
  • pharmaceutically acceptable carriers such as physiologically buffered saline solutions and water.
  • diluents such as phosphate buffered saline solutions pH 7.0-8.0.
  • the therapeutic agents of the invention can also be administered to the respiratory tract.
  • the present invention also provides aerosol pharmaceutical formulations and dosage forms for use in the methods of the invention.
  • dosage forms comprise an amount of at least one of the agents of the invention effective to treat or prevent the clinical symptoms of a virus, cancer, tumor, indication or related disease. Any statistically significant attenuation of one or more symptoms of a virus and/or a cancer that has been treated pursuant to the method of the present invention is considered to be a treatment of such virus and/orcancer within the scope of the invention.
  • the composition may take the form of a dry powder, for example, a powder mix of the therapeutic agents and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges, or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator, insufflator, or a metered-dose inhaler (see, for example, the pressurized metered dose inhaler (MDI) and the dry powder inhaler disclosed in Newman, S. P. in Aerosols and the Lung, Clarke, S. W. and Davia, D. eds., pp.
  • MDI pressurized metered dose inhaler
  • the dry powder inhaler disclosed in Newman, S. P. in Aerosols and the Lung, Clarke, S. W. and Davia, D. eds., pp.
  • Therapeutic agents of the present invention can also be administered in an aqueous solution when administered in an aerosol or inhaled form.
  • other aerosol pharmaceutical formulations may comprise, for example, a physiologically acceptable buffered saline solution containing between about 0.1 mg/ml and about 100 mg/ml of one or more of the therapeutic agents of the present invention specific for the indication or disease to be treated.
  • Dry aerosol in the form of finely divided solid compounds of the invention that are not dissolved or suspended in a liquid are also useful in the practice of the present invention.
  • Compounds of the present invention may be formulated as dusting powders and comprise finely divided particles having an average particle size of between about 1 and 5 ⁇ m, alternatively between 2 and 3 ⁇ m.
  • Finely divided particles may be prepared by pulverization and screen filtration using techniques well known in the art.
  • the particles may be administered by inhaling a predetermined quantity of the finely divided material, which can be in the form of a powder.
  • the unit content of active ingredient or ingredients contained in an individual aerosol dose of each dosage form need not in itself constitute an effective amount for treating the particular infection, indication or disease since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • the effective amount may be achieved using less than the dose in the dosage form, either individually, or in a series of administrations.
  • the therapeutic agents of the invention are conveniently delivered from a nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Nebulizers include, but are not limited to, those described in U.S. Patent Nos. 4,624,251 ; 3,703,173; 3,561 ,444; and 4,635,627.
  • Aerosol delivery systems of the type disclosed herein are available from numerous commercial sources including Fisons Corporation (Bedford, Mass.), Schering Corp. (Kenilworth, NJ) and American Pharmoseal Co., (Valencia, CA).
  • the therapeutic agent may also be administered via nose drops, a liquid spray, such as via a plastic bottle atomizer or metered-dose inhaler.
  • atomizers are the Mistometer (Wintrop) and the Medihaler (Riker).
  • the active ingredients may also be used in combination with other therapeutic agents, for example, pain relievers, anti-inflammatory agents, antihistamines, antimicrobial agents, bronchodilators and the like, whether for the conditions described or some other condition.
  • other therapeutic agents for example, pain relievers, anti-inflammatory agents, antihistamines, antimicrobial agents, bronchodilators and the like, whether for the conditions described or some other condition.
  • compositions are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub- dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient.
  • the present invention further pertains to a packaged pharmaceutical composition for the prevention, inhibition or treatment of a viral infection and/or cancer such as a kit or other container.
  • a packaged pharmaceutical composition for the prevention, inhibition or treatment of a viral infection and/or cancer such as a kit or other container.
  • the kit or container holds a therapeutically effective amount of a pharmaceutical composition for the prevention, inhibition or treatment of a viral infection and/or cancer, and instructions for using the pharmaceutical composition for the prevention, inhibition or treatment of a viral infection and/or cancer.
  • the pharmaceutical composition includes at least one compound of the present invention, in a therapeutically effective amount such that a viral infection and/or cancer is prevented, inhibited or treated.
  • the composition can also contain other anti-cancer agents and/or anti-viral agents as discussed above.
  • the activity of virus and/or cancer after application of the composition can be observed by any method including direct and indirect methods of detecting virus and/or cancer activity. Quantitative, qualitative, and semiquantitative methods of determining viral and/or cancer activity are all contemplated.
  • Organisms that contain viruses and/or cancer include mammals such as humans.
  • the compounds of this invention are useful in the treatment or prophylaxis of viral infections and/or cancer in animals or in man.
  • any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination When administered sequentially, the combination may be administered in two or more administrations.
  • the combination therapy may provide "synergy” and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e.
  • the invention contemplates compounds, compositions and methods that employ combinations of the compounds of the invention with other available anti-viral therapeutics. According to the invention, a combination of compounds of the invention with available anti-viral agents can improve the spectrum of viruses against which those anti-virus agents are effective. Thus, the invention contemplates combinations of the present compounds of the invention with one or more additional anti-viral agents. Any anti-viral agent available can be used with the present compounds of the invention. Further, in some cases, surgical treatment is performed in addition to these methods (combination or single therapy) to improve the effect of the treatment.
  • anti-viral agents examples include vaccines, amantadine, rimantadine, pleconaril, aciclovir, zidovudine (AZT), lamivudine, fomivirsen, zanamivir (Relenza), oseltamivir (Tamiflu), interferons, antibodies, e.g., monoclonal antibodies (e.g., a monoclonal drug to help fight respiratory syncytial virus), Abacavir, Aciclovir, Acyclovir, Adefovir, Amantadine, Amprenavir, Arbidol, Atazanavir, Atripla, Brivudine ,Cidofovir, Combivir, Darunavir, Delavirdine, Didanosine, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Entry inhibitors, e.g., a monoclo
  • the invention also contemplates compounds, compositions and methods that employ combinations of the compounds of the invention with other available anti-cancer therapeutics. Dosages of conventional anti-cancer agents are often kept as low as possible because side effects may be observed at higher dosages. According to the invention, a combination of compounds of the invention with available anti-cancer agents can improve the spectrum of cancers against which those anti-cancer agents are effective and reduce the required dosage of those anti-cancer agents. Thus, the invention contemplates combinations of the present compounds of the invention wiuTone or more anti-cancer or carcinostatic agents. Any anti-cancer an/or carcinostatic agent available can be used with the present compounds of the invention. Further, in some cases, radiotherapy or surgical treatment is performed in addition to these methods (combination or single therapy) to improve the effect of the treatment.
  • anti-cancer7chemotherapeutic agents examples include Altretamine, Bleomycin, Busulphan, Calcium Folinate, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Crisantaspase, Cyclophosphamide, Cytarabine, dacarbazine, Dactinomycin, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Liposomal doxorubicin, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Pentostatin, Procarbazine, Raltitrexed, Streptozocin, Tegafur- ura
  • EXAMPLE 1 Anti-Viral Activity
  • Myristoyl-Cys-Ala-Val-Ala-Tyr-(3 methyl)His-OMe was used to obtain the anti-EBV results and cytotoxicity assay data that follow.
  • HFF Foreskin Fibroblast
  • EBV Epstein-Barr Virus
  • VCA virus capsid antigen
  • ELISA Enzyme Linked Immunosorbent Assay
  • an EC 50 (e.g., Effective
  • Concentration the dosage at which the desired response is present for 50 percent of the population. Selected compounds that have good activity against EBV
  • VCA production without toxicity were tested for their ability to inhibit EBV DNA synthesis. Cytotoxicity. In each assay system utilized, drug treatment of uninfected cells was incorporated to obtain as much toxicity data as possible. For calculation of the SI, it is very important that the data on toxicity be at least as reliable as the results for efficacy.
  • HFF Human Foreskin Fibroblast
  • the media/drug was aspirated and 200 ⁇ l/well of 0.01% neutral red in DPBS was added. This was incubated in a CO 2 incubator for 1 hr. The drug was aspirated and the cells were washed using a Nunc Plate Washer. After removing the DPBS wash, 200 ⁇ l/well of 50% ETOH/1% glacial acetic acid (in H 2 O) was added. The plates were rotated for 15 min and the optical densities were read at 550 nm on a plate reader. EC 50 values were calculated using a computer program.
  • HFF Human Foreskin Fibroblast
  • drugs compound of interest; e.g., a compound of formula XX
  • MEM fetal calf serum
  • control wells received MEM containing 1.0% DMSO.
  • the media from the wells was then aspirated and 2 ml of each drug concentration was then added to each well.
  • the cells were then incubated in a CO 2 incubator at 37°C for 72 hr. At the end of this time, the media-drug solution was removed and the cells washed.
  • One ml of 0.25% trypsin was added to each well and incubated until the cells started to come off of the plate.
  • the cell-media mixture was then
  • HFF Human Foreskin Fibroblast
  • the synthesized structure of Formula (I) has excellent anti-viral activity against the Epstein-Barr Virus (EBV )- Effective 5 Concentration 90% (EC 90 ) at 20 ⁇ M or inhibited viral replication by 90%.
  • the DNA Hybridization assay was done to determine anti-EBV activity using the Akata cell line (B-lymphocyte from Burkitt's Lymphoma patient) (N. Shimizu, A. Tanabe-Tochikura, Y. Kuroiwa and K.
  • HFF foreskin fibroblast
  • An Effective Concentration (EC) of >20 ⁇ M of the synthetic antiviral compound inhibited viral replication in Akata cells (B-lymphocyte/Burkitt's Lymphoma) by 50% (EC 50 ) compared with an EC5 0 of 17 ⁇ M for the Acyclovir control.
  • Antiviral compound 0 was nearly equivalent then to Acyclovir control in antiviral activity.
  • An Effective Concentration (EC) of >20 ⁇ M of the synthetic antiviral compound also inhibited viral replication in Akata cells by 90% (EC 90 ). So the same antiviral compound concentration (>20 ⁇ M) also inhibited viral replcation by 90%.
  • An Acyclovir control (EC 90 ) was not done. This indicates that the antiviral compound effectively 5 stopped all viral replication (EC 90 ) at >20 ⁇ M.
  • the antiviral compound disclosed herein was therefore as effective in preventing viral replication of EBV as Acyclovir.
  • Acyclovir is an antiviral drug commonly used for treatment of herpes simplex virus infection.
  • the Cytotoxic Concentration (CC 50 ) in the cytotoxicity assay test was 74 ⁇ M. This means that a concentration of 74 ⁇ M inhibited cell divison by 50%.
  • the CC 50 was nearly 4-times greater than the EC 50 of the synthetic antiviral compound. So viral replication would be inhibited at >20 ⁇ M (EC 50 and ECg 0 ) before the antiviral compound would become toxic to cells at 74 ⁇ M. Antiviral activity would thus still be effective before the antiviral compound became toxic to cells.
  • a Herpes-Toxicity-Cell Proliferation Assay was done in Human Foreskin
  • Fibroblast (HFF) cells with the synthetic antiviral compound were used with the synthetic antiviral compound.
  • An IC 50 of > 100 ⁇ M was needed to inhibit cell proliferation of 50%. This compares with 40 ⁇ M for the Ganciclovir control.
  • the antiviral compound is at least 2.5-times less toxic than Ganciclovir.
  • the antiviral compound was equal to Acyclovir which also had an IC 50 of >100 ⁇ M.
  • the EC 50 and EC 90 for the antiviral compound were both >20 ⁇ M. When compared with an IC 50 of > 100 ⁇ M for this toxicity assay, then this would give a Selectivity Index (SI) of 5 for antiviral activity.
  • SI Selectivity Index
  • the fibroblast or connective tissue cell is the most common animal tissue cell and is used as a general tissue culture cell to test for drug cytotoxic activity.
  • a Herpes-Toxicity-Neutral Red Assay was done in Human Foreskin Fibroblast
  • HFF High Mobility FFF cells with the synthetic antiviral compound.
  • a CC 50 of >300 ⁇ M was obtained for the antiviral compound when compared with Ganciclovir and Acyclovir which both had a CCsoof > 100 ⁇ M.
  • the EC 50 and EC 90 for the antiviral compound were both >20 ⁇ M. When compared with a CC 50 of >300 ⁇ M for this cytotoxicity assay, this would give a Selectivity Index (SI) of 15, a very significant SI number for antiviral activity.
  • SI Selectivity Index
  • the Cell Proliferation Toxicity Assay determines the effect of drug treatment on dividing cells and the drug concentration that inhibits cell growth by 50% (IC 5 o).
  • the Neutral Red Toxicity Assay determines direct cell cytotoxicity (CC50). This toxicity assay quantitates the number of viable cells present after drug treatment.
  • SI Selectivity Index
  • EBV is a double-stranded DNA, enveloped virus (Herpesviridae family).
  • the antiviral compound most likely inhibits viral DNA synthesis.
  • the anti-EBV data and Cytotoxicity results for the antiviral and anticancer compound were obtained at the National Institute of Allergy and Infectious Diseases (NIAID)-Antimicrobial Acquisition and Coordinating Facility, Birmingham, AL.
  • the synthesized compound of formula (I) showed very low cytotoxicity to host cells.
  • NIAID testing found that its cytotoxicity was only one-third that of Acyclovir and Ganciclovir, which were two antivirals used as cellular controls.
  • the vast majority of new potential antiviral and antibiotic agents are eliminated because they are too cytotoxic to host cells. Being able to inactivate a virus inside a host cell without killing the host cell is very difficult for an antiviral drug to do. This attribute makes this a very strong and clinically relevant antiviral drug.
  • EXAMPLE 2 Anti-Cancer Activity
  • the synthesized compound is also an anti-cancer drug.
  • the National Cancer Institute of NIH has tested the compound for anti-cancer activity using established procedures (M. C. Alley, D. A. Scudiero, A. Monks, M. L. Hursey, M. J. Czerwinski, D. L. Fine, B. J. Abbott, J. G. Mayo, R. H. Shoemaker and M. R.
  • the synthesized compound was screened here for anti-cancer activity against 56 different live tumor cell lines in tissue culture by the National Cancer Institute of NlH (see Figure 1). NCl found that 34 out of the 56 tumor cell lines were very sensitive (growth inhibition or killing of cancer cells) to the compound.
  • the tumor cell lines sensitive to the compound included: Non-Small Cell Lung Cancer, Colon Cancer, Breast Cancer, Ovarian Cancer, Leukemia, Renal Cancer, Melanoma, CNS (Brain) Cancer.
  • a compound of synthesized formula (I) or Myristoyl-Cys-Ala-Val-Ala-Tyr-(3 methyl)His-OMe at 10 ⁇ M was effective (Growth Inhibition of tumor cells greater than 50%) against 4 out of 7 renal cancers, 5 out of 8 melanoma cancers, 3 out 6 brain cancers, 2 out of 5 ovarian cancers, 5 out of 5 leukemias, 7 out of 9 non-small cell lung caners, 5 out of 7 colon cancers, and 3 out of 7 breast cancers.
  • the compound has essentially no cytotoxic activity to human fibroblast cells (connective tissue cells), the most common animal body cell. Thus, it does not act as a poison to human non-cancer cells.
  • the National Cancer Institute finds that their in vitro screen is an effective selector of compounds with in vivo antitumor activity. See Figure 1 for bar graph of anti-cancer data by NCl of synthesized compound.
  • EXAMPLE 3 Anti-Fungal Activity
  • Many anti-fungal drugs contain an imidazole ring.
  • Imidazole and triazole inhibit an enzyme (cytochrome P450) needed for biosynthesis of ergosterol, an important sterol found in fungal cell membranes.
  • New antifungal drugs are needed as many fungal infections have acquired multidrug resistance.
  • Antifungal drugs containing the azole ring have also been found to be effective against the tuberculosis (TB) bacterium that currently infects one-third of the world's population (Seward, H. E., J. Biol. Chem., 281 , 39437-39443, 2006; Munro, A. W., Science Daily, March 12, 2007). Multidrug resistant strains of TB have emerged and thus new anti-TB drugs are needed.
  • TB tuberculosis

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Abstract

The invention provides compounds, compositions and methods for inhibiting, preventing and/or treating cancer and/or viral, helminthic, fungal, microbial, bacterial and/or protozoan infection, and/or insecticidal activity.

Description

ANTI-CANCER/ANTI- VIRAL COMPOUNDS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Application Serial No. 12/1 18,470, filed May 9, 2008, the entire disclosure of which is incorporated by reference herein.
Field of the Invention
The invention relates to compounds, compositions and methods for inhibiting, preventing and/or treating cancer and/or viral, helminthic, fungal, microbial, bacterial and/or protozoal infection, and/or insecticidal activity.
Background of the Invention
New anti-cancer and anti-viral treatments are needed to support medicine. Cancer, including those cancers thought to be caused by viruses, is a disease that afflicts many people and is a leading cause of death in humans and non-human animals. Cancer typically involves uncontrolled growth of cells that then creates many new cells. Many anti-cancer drugs are agents that inhibit or stop cell growth. Such chemotherapeutic agents have improved the survival rate of patients having cancer. However, the serious side effects associated with many chemotherapeutic agents limits their usage and undermines the health of patients already weakened by cancer. Thus, new agents are needed that exhibit enhanced selectivity for cancer cells or that are capable of controlling proliferation of cancerous cells with limited side effects.
Viral infections are among the leading causes of death with millions of deaths each year being directly attributable to several viruses including hepatitis and HIV. Currently there is no effective therapy for most viral diseases. Many of the existing anti- virals cause adverse or undesirable side-effects and most effective therapies (such as vaccination) are highly specific for only a single strain of virus. Frequently a virus undergoes mutation such that it becomes resistant to either the drug or vaccine. Thus, there is a need for effective inhibition, prevention or treatment of virus-mediated diseases. Summary of the Invention
The Heliothis virescens hemolymph (blood) was found to have antiviral activity (Ourth, D. D., Renis, H. E. Comp. Biochem. Physiol., 105B, 719-723, 1993). The hemolymph antiviral factor was antiviral against Herpes Simplex Virus- 1 (SI of 1 10), Herpes Simplex Virus-2 (SI of 1 10), Vesicular Stomatitis Virus (SI of 45), Coxsackie B3 (SI of 20), Sindbis (SI of 20), and Parainfluenza-3 (SI of 16) DNA and RNA viruses. Provided herein are compounds, compositions and methods for inhibiting, preventing and/or treating cancer and/or viral infections.
One embodiment provides a compound of formula (XX):
Figure imgf000003_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
R is independently at each occurrence H or (Ci-C6)alkyl; R1 and R2 independently comprises H or (C|-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted (e.g., two or more) with halo, hydroxy, CO2Y, CONYY', NYY1, oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (C|-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C iO)alkenyl, (C2-C ,0)alkynyl, (Ci-Cio)haloalkyl, (C3-Ci0)cycloalkyl, (C3- Cio)cycIoalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (CrC6)haloalkyl, (CrC6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cιo)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- C]0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C|-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (Cr C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C]-C6)haloalkyl, (C|-C6)haloalkoxy, or carboxyamido, or any combination thereof; Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (CrC6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C]-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (CrC6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (d-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof.
In one embodiment, when X1 is C6-C25alkylcarbonyl, X3 is not Ala, X4 is not VaI and X5 is not Ala. In another embodiment, when X1 is myristoyl or palmitoyl, X3 is not Ala, X4 is not VaI and X5 is not Ala. In embodiment, the steroid is cholesterol, vitamin A, or vitamin D. In another embodiment, X3-X5 are independently any non-polar amino acid and X6 is absent. In another embodiment, X6 is any non-polar amino acid. In one embodiment, X3 is alanine, X4 is valine, X5 is alanine, and X6 is absent. In another embodiment, the compound forms a dimer. In one embodiment, X1 is myristoyl or palmitoyl. In another embodiment, X2 is cysteine. In one embodiment, R1 and R2 are methyl. In another embodiment, R3 is OMe.
In one embodiment X'-X6 are independently either absent or any number of (e.g., one or more) O, S, CR, NR, or amino acids, all of which may be optionally independently substituted (e.g., optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido).
One embodiment provides a composition comprising a compound provided herein and a pharmaceutically acceptable carrier. Another embodiment provides a unit dosage form comprising a compound provided herein and a pharmaceutically acceptable carrier.
One embodiment provides a method to inhibit replication of a virus in a cell comprising contacting said cell with a compound provided herein in an amount effective to inhibit the replication of the virus in said cell. In one embodiment, the virus is human immunodeficiency virus (HIV), herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or Epstein Barr Virus (EBV).
Another embodiment provides a method to inhibit replication of a virus in a cell comprising contacting said cell with a compound of formula (XX):
Figure imgf000006_0001
wherein
X1 is C6-C2salkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-XD are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (C)-C6)alkyl;
R1 and R2 are independently H or (C)-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C iO)alkenyl, (C2-C,0)alkynyl, (Ci-Cio)haloalkyl, (C3-C,o)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (CrC6)haloalkyl, (C|-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (CrC6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (C|-CiO)alkyl, (Ci- Ci0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-Ce)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof; Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1, or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C|-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the replication of the virus in said cell, provided the virus is not HIV or herpes simplex virus-1 (HSV-I). In one embodiment, the virus is not herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis viruses. In another embodiment, the virus is an Epstein Barr Virus (EBV).
On embodiment provides a method to inhibit a viral infection in vitro or in vivo comprising contacting a sample in need of such treatment with a compound disclosed herein in an amount effective to inhibit viral infection. In one embodiment, the virus is human immunodeficiency virus (HIV), herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or Epstein Ban- Virus (EBV).
Another embodiment provides a method to inhibit a viral infection in vitro or in vivo comprising contacting a sample in need of such treatment with a compound of formula (XX):
Figure imgf000009_0001
wherein X is C6-C25alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent; X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9,
10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (Ci-C6)alkyl; R1 and R2 are independently H or (Ci-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Cι-Cιo)alkyl, (C2-C]0)alkenyl, (C2-Ci0)alkynyl, (Ci-Cio)haloalkyl, (C3-C|0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (C|-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cιo)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (CrC6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-
C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C]-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1-4 (Ci-C6)alkyl, halo, OR, NRB 2, (C|-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R comprises cyano, CO2R, or a group of formula -C(=X )N(R )2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit viral infection, provided the virus is not HIV or herpes simplex virus-1 (HSV-I). In one embodiment, the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection. In another embodiment, the virus is an Epstein Barr Virus (EBV).
One embodiment provides that the contacting is in vivo. Another embodiment provides a method to treat a viral infection comprising administering to a subject in need thereof an effective amount of a compound disclosed herein. In one embodiment, the virus is human immunodeficiency virus (HIV), herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or Epstein Barr Virus (EBV). One embodiment provides a method to treat a viral infection comprising administering to a subject in need thereof an effective amount of a compound of formula (XX):
Figure imgf000012_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (Ci-C6)alkyl; R1 and R2 are independently H or (Ci-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (C]-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cιo)alkyl, (C2-C,o)alkenyl, (C2-C 10)alkynyl, (C,-C,0)haloalkyl, (C3-C, 0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cιo)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (CrC6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- Cιo)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (CrC6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-
C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (Ci-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (C|-C6)alkyl, halo, OR, NR 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R , or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-
C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, orNNH-aryl; or a pharmaceutically acceptable salt thereof, provided the virus is not HIV or herpes simplex virus-1 (HSV-I). In one embodiment, the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection. In another embodiment, the virus is an Epstein Barr Virus (EBV).
In one embodiment, the subject is a mammal, including a human.
Another embodiment provides a compound disclosed herein formulated with a pharmaceutically acceptable carrier. Another embodiment provides the administration of a second active ingredient.
One embodment provides a method to inhibit tumor growth in vitro or in vivo comprising contacting a cell in need of such treatment with a compound of formula (XX):
Figure imgf000014_0001
wherein
X1 is Q-C^alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (Ci-C6)alkyl;
R1 and R2 are independently H or (Ci-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl/ heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C 10)alkenyl, (C2-C ,0)alkynyl, (Ci-Cio)haloalkyl, (C3-C,0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-CiO)alkyl, (Ci-C)0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cιo)alkyl, (Ci- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C|-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (C|-C6)haloalkoxy, or carboxyamido, or any combination thereof; Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1-4 (Ci-C6)alkyl, halo, OR, NRB 2, (C|-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, so as to inhibit tumor growth. In one embodiment, the contacting is in vivo. In another embodiment, the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal.
One embodiment provides a method to treat symptoms of cancer in a subject comprising administering to a subject in need thereof an effective amount of a compound of formula (XX):
Figure imgf000017_0001
wherein
X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
R is independently at each occurrence H or (Ci-C6)alkyl;
R1 and R2 are independently H or (Ci-C4)alkyl or or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-Ci0)alkenyl, (C2-C,0)alkynyI, (C,-Ci0)haloalkyl, (C3-C, 0)cycloalkyl, (C3- C|0)cycloalkyl(C|-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-C|0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (C|-CiO)alkyl, (Ci- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-Ce)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (CrC6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (CrC6)haloalkyl, (C3-
C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof.
Another embodiment provides a method to inhibit neoplastic disease in a subject comprising administering to a subject in need thereof an effective amount of a compound of formula (XX):
Figure imgf000019_0001
wherein X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (C|-C6)alkyl; R1 and R2 are independently H or (Ci-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group; R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (C,-C,0)alkyl,
(C2-C, 0)alkenyl, (C2-C, 0)alkynyl, (C,-C10)haloalkyl, (C3-Ci0)cycloalkyl, (C3- C,o)cycloalkyl(C,-C,o)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (C,-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (C,-C,o)alkyl, (C,-C,o)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (C,-C,o)alkyl, (C,- C,o)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C,-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (CrC6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1, or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (d-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (d-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof. In one embodiment, the the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T- cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma, including Burkitt's lymphoma. In one embodiment, the subject is a mammal, including a human. In one embodiment, the compound is formulated with a pharmaceutically acceptable carrier. In another embodiment, a second active ingredient is administered.
One embodiment provides a compound of formula (XX):
Figure imgf000022_0001
wherein
X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
R is independently at each occurrence H or (Ci-C6)alkyl;
R1 and R2 are independently H or (Ci-Gj)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y1 independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Cι-Cio)alkyl, (C2-C iO)alkenyl, (C2-Ci0)alkynyl, (C,-C|0)haloalkyl, (C3-C|0)cycloalkyl, (C3- Cio)cycloalkyl(C|-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (d-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Ci0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C]-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (d-C6)haloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C]-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1-4 (C|-C6)alkyl, halo, OR, NR 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R , or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (C|-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (d-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, provided that when X1 is C6-C25alkylcarbonyl, X3 is not Ala, X4 is not VaI and XD is not Ala for use in medical therapy. In another embodiment, when X1 is myristoyl or palmitoyl, X3 is not Ala, X4 is not VaI and X5 is not Ala. In one embodiment, the medical therapy is treatment of cancer. In another embodiment, the medical therapy is treatment or prevention of a viral infection.
One embodiment provides the use of a compound of formula (XX):
Figure imgf000024_0001
wherein X1 is Cό-C^alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids);
R is independently at each occurrence H or (C|-C6)alkyl; R1 and R2 are independently H or (Ci-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group; R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (CrCi0)alkyl,
(C2-C iO)alkenyl, (C2-C]0)alkynyl, (C,-C10)haloalkyl, (C3-C, 0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (d-C6)haIoalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (C)-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Cιo)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- C]0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-Cό)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof; Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (CrC6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (C|-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating or inhibiting viral infection, provided the viral infection is not a HlV or herpes simplex virus- 1 (HSV-I) infection. In one embodiment, the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection. In another embodiment, the viral infection is an Epstein Barr Virus (EBV) infection. One embodiment provides for the use of a compound of formula (XX):
Figure imgf000027_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (Ci-C6)alkyl; R1 and R2 are independently H or (CrC4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-Ci0)alkenyl, (C2-C,0)alkynyl, (Ci-Cio)haloalkyl, (C3-Ci0)cycloalkyl, (C3-
Ci0)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Cι-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Q- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (d-C6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-Cό)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (C|-C6)haloalkyl, (Cj-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (d-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, provided that when X is C6-
C25alkylcarbonyl, X3 is not Ala, X4 is not VaI and X5 is not Ala to prepare a medicament for treating or inhibiting viral infection. In another embodiment, when X1 is myristoyl or palmitoyl, X3 is not Ala, X4 is not VaI and X5 is not Ala. In one embodiment, the viral infection is a HIV, herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or EBV infection.
One embodiment provides the use of a compound of formula (XX):
Figure imgf000029_0001
wherein
X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent (e.g., X6 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); R is independently at each occurrence H or (Ci-C6)alkyl; R1 and R2 are independently H or (Ci-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y1 independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C 10)alken^l, (C2-Ci0)alkynyl, (Ci-C10)haloalkyl, (C3-C 10)cycloalkyl, (C3- Cιo)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (C|-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Cι-Cio)alkyl, (Cι-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cιo)alkyl, (C1- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C]-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two R together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (C|-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (CrC6)alkyl, (CrC6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-
C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof to prepare a medicament for inhibiting tumor growth, inhibiting neoplastic disease or treating cancer in a subject. In one embodiment, the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal. In another embodiment, the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy-cell leukemia or non- Hodgkin's lymphoma, including Burkitt's lymphoma. One embodiment provides a method to treat a fungal infection comprising administering an effective amount of a compound of the invention (e.g., a comound of formula XX) to a subject in need thereof. Another embodiment provides a method to treat a fungal (e.g., pathogenic Candida (yeast) species, and/or Aspergillus species, Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, Cryptococcus gattii, Histoplasma capsulatum, Pneumocystis jirovecii, andor Stachybotrys chartarum), helminthic (e.g,. parasitic worms including cestodes (e.g., tapeworms), nematodes (e.g., whipworms, hookworms, pinworms, ascarids, filarids, Trichinella spiralis (trichina worm (trichinosis)), baylisascaris, haemonchus contortus or entomopathogenic nematodes), or trematodes (e.g., flukes - tissue flukes which infect, for example, the bile ducts, lungs (e.g., Paragonimus westermani), liver (e.g., Clonorchis sinensis and Fasciola hepatica), or _ other biological tissues or blood flukes)), bacterial (e.g., tuberculosis (TB) bacterium or pathogenic bacterium from the following genuses: Bacillus, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia, Clostridium, Corynebacterium, Enterococcus, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Streptococcus, Treponema, Vibrio, or Yersinia), or protozoal (e.g., malaria parasites (Plasmodium spp.), trypanosomes or leishmania) infection comprising administering an effective amount of a compound of the invention (e.g., a comound of formula XX) to a subject in need thereof. One embodiment comprises a compound of formula (VII): Xi-X2-X3-X4-X5-X6-
Tyr-(Z)His-OMe (VII), wherein X| is palmitoyl, a transporter peptide sequence; HIV- TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, or homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl). In one embodiment, the steroid is cholesterol, vitamin A, or vitamin D or terpenoid lipid. In one embodiment, the compound forms a dimer, while in other embodiments the compound is monomer. In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
One embodiment provides a composition comprising the compound of formula (VII) and a pharmaceutically acceptable carrier. Another embodiment provides a method of making a composition comprising admixing a compound of the invention with a pharmaceutically acceptable carrier. Another embodiment provides a unit dosage form comprising a compound of formula (VII) and a pharmaceutically acceptable carrier.
Another embodiment provides a method to inhibit replication of a virus in a cell comprising contacting said cell with a compound of formula (I): Myristoyl-Cys-X]-X2-X3 X4-Tyr-(Z)His-OMe (I) in an amount effective to inhibit the replication of the virus in said cell, provided the virus is not HIV or herpes simplex virus-1 (HSV-I), wherein Xi- X3 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X4 is either absent or at least one nonpolar amino acid (X4 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1,3 dimethyl) or (3 methyl). In one embodiment Xi is alanine, X2 is valine and X3 is alanine. In another embodiment, X4 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In another embodiment, the virus is not herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis viruses. In one embodiment, the virus is EBV.
Another embodiment provides a method to inhibit the replication of a virus in a cell comprising contacting said cell with a compound of formula (VII): Xi-X2- X3-X4- Xs-X6-Ty r-(Z)Hi s-OMe (VII), wherein Xj is palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or X| and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more nonpolar amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl) in an amount effective to inhibit the replication of the virus in said cell. In one embodiment, the virus is HIV, herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfIuenza-3, coxsackie B3, sindbis virus, or EBV. In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
Another embodiment provides a method for inhibiting a viral infection in vitro or in vivo comprising contacting a sample, cell or subject in need of such treatment with a compound of formula (I): Myristoyl-Cys-X|-X2-X3-X4-Tyr-(Z)His-OMe (1) provided the viral infection is not HIV or herpes simplex virus-1 (HSV-I) infection, wherein Xi-X3 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X4 is either absent or at least one nonpolar amino acid (e.g., X4 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl). In one embodiment, Xi is alanine, X2 is valine and X3 is alanine. In another embodiment, X4 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In one embodiment, the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection. In another embodiment, the viral infection is an EBV infection.
One embodiment provides a method for inhibiting a viral infection in vitro or in vivo comprising contacting a sample, cell or subject in need of such treatment with a compound of formula (VII): X,-X2-X3-X4-X5-X6-Tyr-(Z)His-OMe (VII), wherein X, is palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl). In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In one embodiment, the contacting is in vivo. In another embodiment, the viral infection is an HIV, herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or EBV infection. Another embodiment provides a method of treating a viral infection in a subject, comprising administering a compound of formula (I) to the subject Myristoyl-Cys-Xi-X2- X3-X4-TVr-(Z)HiS-OMe (I), provided the viral infection is not a HIV or herpes simplex virus-1 (HSV-I) infection, wherein XpX3 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X4 is either absent or at least one nonpolar amino acid (e.g., X4 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1,3 dimethyl) or (3 methyl). In one embodiment, X| is alanine, X2 is valine and X3 is alanine. In another embodiment, X4 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In another embodiment, the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus, parainfluenza-3, coxsackie B3, or sindbis virus infection. In one embodiment, the viral infection is an EBV infection.
Another embodiment provides a method of treating a viral infection in a subject, comprising administering a compound of formula (VII) to the subject: X)-X2-X3-X4-Xs- X6-Tyr-(Z)His-OMe (VII), wherein Xi is palmitoyl, a transporter peptide sequence; HIV- TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl). In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In one embodiment, the viral infection is an HIV, herpes simplex virus- 1, herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or EBV infection.
Another embodiment provides a method of inhibiting tumor growth in vitro or in vivo comprising the step of contacting a sample, cell or subject in need of such treatment with a compound of formula (VII): X, -X2- X3-X4-X5-X6-Tyr-(Z)His-OMe (VII), wherein Xi is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl). In one embodiment, the contacting is in vivo. In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
In another embodiment, the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal. Another embodiment provides a method of treating the symptoms or effects of cancer in a subject which comprises administering to said subject a compound of formula (VlI): Xi-X2- X3-X4-X5-X6-Tyr-(Z)His-OMe (VII), wherein X, is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl). In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1,3 dimethyl). Another embodiment provides a method of inhibiting neoplastic diseases in a subject in need of such treatment comprising administering to said subject a compound of formula (VII): X1-X2- X3-X4-X5-X6-Tyr-(Z)His-OMe (VIII), wherein Xi is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or X) and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1,3 dimethyl) or (3 methyl). In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
In one embodiment, the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma. In one embodiment, the non- Hodgkin's lymphoma is Burkitt's lymphoma.
In one embodiment, the subject is a mammal, such as a human. In another embodiment the sample includes bodily fluid or cells, such as blood cells, tumor cells and/or cells infected by a virus, including but not limited to eukaryotic cells, such as human cells.
In some embodiments, the compound is formulated with a pharmaceutically acceptable carrier. In other embodiments, the compound is further formulated with a second active ingredient. Another embodiment provides a compound of a compound of formula (VII): Xi-
X2- X3-X4-X5-X6-Tyr-(Z)His-OMe (VII), wherein Xi is palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S- glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid
(such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl) for use in medical therapy. In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In one embodiment, the medical therapy is the treatment of cancer, while in another embodiment, the medical therapy is the treatment of a viral infection. Another embodiment provides for the use of a compound of formula (I):
Myristoyl-Cys-Xi-X2-X3-X4-Tyr-(Z)His-OMe (I) to prepare a medicament for inhibiting a viral infection, provided the viral infection is not a HIV or herpes simplex virus-1 (HSV-I) infection, wherein Xi-X3 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X4 is either absent or at least one nonpolar amino acid (e,g., X4 comprises, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and wherein (Z) is (1 ,3 dimethyl) or (3 methyl). In one embodiment, Xi is alanine, X2 is valine and X3 is alanine. In another embodiment, X4 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In another embodiment, the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection. In one embodiment, the viral infection is an EBV infection.
Another embodiment provides for the use of a compound of formula (VII): Xi- X2-X3-X4-X5-X6-Tyr-(Z)His-OMe (VII), wherein Xi is palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S- glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g, X6 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl) to prepare a medicament for inhibiting a viral infection. In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1,3 dimethyl). In one embodiment, the viral infection is a is HIV, herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza- 3, coxsackie B3, sindbis virus, or EBV infection.
One embodiment provides for the use of a compound of formula (VII): Xi-X2- X3-X4-X5-X6-TVr-(Z)HiS-OMe (VII), wherein Xi is myristoyl, palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid, or a terpenoid lipid; X2 is cysteine, serine, homoalanine; or X| and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S- glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1,3 dimethyl) or (3 methyl) to prepare a medicament for inhibiting tumor growth in an animal. In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl).
In one embodiment, the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal. Another embodiment provides the use of a compound of formula (VII): XpX2- X3-X4-X5-X6-Tyr-(Z)His-OMe (VII), wherein Xi is palmitoyl, a transporter peptide sequence; HIV-TAT peptide sequence; Drosophila Antennapedia peptide sequence; a steroid or terpenoid lipid; X2 is cysteine, serine, homoalanine; or Xi and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S- glyceryl-cysteine (Pam 3-cysteine); X3-X5 are independently any nonpolar amino acid (such as tryptophan, glycine, alanine, phenylalanine, proline, methionine, valine, leucine, or isoleucine); X6 is either absent or at least one nonpolar amino acid (e.g., X6 comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100 or more amino acids); and (Z) is (1 ,3 dimethyl) or (3 methyl) to prepare a medicament for inhibiting a neoplastic disease in a mammal. In one embodiment, X3 is alanine, X4 is valine and X5 is alanine. In another embodiment, X6 is absent. In one embodiment, (Z) is (3 methyl). In another embodiment, (Z) is (1 ,3 dimethyl). In one embodiment, the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma. In one embodiment, the non-Hodgkin's lymphoma is Burkitt's lymphoma.
Brief Description of the Drawings
The following Detailed Description given by way of example, but not intended to limit the invention to specific embodiments described, may be understood in conjunction with the accompanying drawings, incorporated herein by reference.
Figure 1 depicts a bar graph of anti-cancer data obtained with Myristoyl-Cys- Ala-Val-Ala-Tyr-(3 methyl)His-OMe.
Detailed Description of the Invention
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the invention to those claims. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. DEFINITIONS Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
The following definitions are used, unless otherwise described. Halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, aralkyl, alkylaryl, etc. denote both straight and branched alkyl groups; but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. Aryl includes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (Ci-C4)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. It will be appreciated by those skilled in the art that the compounds of the invention may have more than one chiral center and may be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, or enzymatic techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity using the tests described herein, or using other similar tests which are well known in the art.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Specifically, (Ci-C8)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, hexyl, heptyl or octyl. As used herein, the term "cycloalkyl" encompasses bicycloalkyl (norbornyl, 2.2.2-bicyclooctyl, etc.) and tricycloalkyl (adamantyl, etc.), optionally comprising 1 -2 N, O or S. Cycloalkyl also encompasses (cycloalkyl)alkyl. Thus, (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. (Ct-C8)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2-C6)alkynyl can be ethynyl, 1 -propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (Ci-C6)alkanoyl can be acetyl, propanoyl or butanoyl; halo(Ci-C6)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chIoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl; hydroxy(C|-C6)alkyl can be hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl; (C]-C6)alkoxycarbonyl (CO2R2) can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (Ci-C6)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio, (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyraxolyl, pyrrolyl, pyrazinyl, tetrazolyl, puridyl (or its N-oxide), thientyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl denotes a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1 , 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (Ci-C8)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
The term "heterocycle" generally represents a non aromatic heterocyclic group, having from 3 to about 10 ring atoms, which can be saturated or partially unsaturated, containing at least one heteroatom (e.g., 1 , 2, or 3) selected from the group consisting of oxygen, nitrogen, and sulfur. Specific, "heterocycle" groups include monocyclic, bicyclic, or tricyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. A "heterocycle" group also can include one or more oxo groups (=0) attached to a ring atom. Non-limiting examples of heterocycle groups include 1 ,3-dioxolane, 1 ,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuelidine, thiomorpholine, and the like.
The term "alkylene" refers to a divalent straight or branched hydrocarbon chain (e.g. ethylene -CH2CH2-). The term "aryl(Ci-C8)alkylene" for example includes benzyl, phenethyl, 3- phenylpropyl, naphthylmethyl and the like.
The term "protecting group" refers to any group that, when bound to a hydroxyl, nitrogen, or other heteroatom prevents undesired reactions from occurring at this group and that can be removed by conventional chemical or enzymatic steps to reestablish the 'unprotected' hydroxyl, nitrogen, or other heteroatom group. The particular removable group employed is often interchangeable with other groups in various synthetic routes. Certain removable protecting groups include conventional substituents such as, for example, methyl, allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, methyl methoxy, silyl ethers (e.g., trimethylsilyl (TMS), /-butyl-diphenylsilyl (TBDPS), or /-butyldimethylsilyl (TBS)) and other groups that can be introduced chemically onto a hydroxyl functionality, prevent certain undesirable activity, and later can be selectively removed, either by chemical or enzymatic methods, in conditions that are compatible with the nature of the product.
A large number of protecting groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991 , ISBN 0-471-62301 -6) ("Greene", which is incorporated herein by reference in its entirety). Greene describes many nitrogen protecting groups, for example, amide-forming groups. In particular, see Chapter 1 , Protecting Groups: An Overview, pages 1 -20, Chapter 2, Hydroxyl Protecting Groups, pages 21 -94, Chapter 4, Carboxyl Protecting Groups, pages 1 18-154, and Chapter 5, Carbonyl Protecting Groups, pages 155-184. For other protecting groups and useful techniques, see Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is also incorporated herein by reference in its entirety. Some specific protecting groups that can be employed in conjunction with the compounds and methods of the invention are discussed below. Typical carboxy protecting groups described in Greene (e.g., pages 21-94 and 1 18-154) include benzyl ethers, silyl ethers, esters including sulfonic acid esters, carbonates, sulfates, and sulfonates. For example, suitable carboxy protecting groups include methyl ethers; substituted methyl ethers; substituted ethyl ethers; /?-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl; substituted benzyl ethers (p-methoxybenzyl, 3,4-dimethoxybenzyl, ø-nitrobenzyl, /?-nitrobenzyl, /?-halobenzyl, 2,6-dichlorobenzyl, /7-cyanobenzyl,/>-phenylbenzyl, 2- and 4-picolyl, diphenylmethyl, 5-dibenzosuberyl, triphenylmethyl,/7-methoxyphenyl-diphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, l ,3-benzodithiolan-2-yl, benzisothiazolyl 5,5-dioxido); silyl ethers (silyloxy groups) (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, /-butyldimethylsilyl, /-butyldiphenylsilyl, tribenzylsilyl, tri-/?-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, /-butylmethoxy-phenylsilyl); esters (formate, benzoylformate, acetate, choroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate^-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate)); carbonates (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, /»-nitrophenyl, benzyl, /?-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,
/7-nitrobenzyl, 5-benzyl thiocarbonate, 4-ethoxy-l -naphthyl, methyl dithiocarbonate); groups with assisted cleavage (2-iodobenzoate, 4-azidobutyrate, 4-nitro-4- methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, miscellaneous esters (2,6-dichIoro-4-methylphenoxyacetate, 2,6-dichloro-4-(l ,l ,3,3 tetramethylbutyl)phenoxyacetate, 2,4-bis(l,l -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (£)-2-methyl-2-butenoate (tigloate), o-(methoxycarbonyl)benzoate,/7-poly-benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'- tetramethyl-phosphorodiamidate, rc-phenylcarbamate, borate, 2,4-dinitrophenylsulfenate); and sulfonates (sulfate, methanesulfonate (mesylate), benzylsulfonate, tosylate, triflate). The term "amino acid" includes and naturally occurring or synthetic amino acid including D or L amino acids, including but not limited to polar amino acids (Asp, GIu, Tyr, Asn, GIn, Thr, Ser, Cys, Lys, Arg, His) and non-polar amino acids (Trp, GIy, Ala, Phe, Pro, Met, VaI, Leu, He). It is noted that, as used herein the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, as used herein, the singular form may be used interchangeably with the plural form, and vice versa.
As used herein, "including" or "includes" or the like means including, without limitation. As used herein, "organism" or "individual" or "subject" or "body" or "patient" or
"sample" refers to any bodily fluid, cell(s) (eukaryotic and/or prokaryotic), tissue(s) or animal(s), including mammals, preferably humans, or plant to which the present invention may be applied.
As used herein, "treat" or "treating" includes treating, preventing, ameliorating, or inhibiting a disease, disorder and/or a symptom of a disease and/or a disorder of an organism.
As used herein, an "effective amount" generally means a sufficient amount of a compound to provide the desired local or systemic effect and performance.
As used herein, "pharmaceutically acceptable carrier" refers to carrier materials without significant pharmacological activity at the quantities used that are suitable for administration with other compounds, and include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluents, solubilizer, microspheres, liposomes, microparticles, lipid complexes, or the like, that is sufficiently nontoxic at the quantities employed and does not interact with the drug to be administered in a deleterious manner. Examples of suitable carriers for use herein include water, buffers, mineral oil, silicone, inorganic or organic gels, aqueous emulsions, liquid sugars, lipids, microparticles, waxes, petroleum jelly, and a variety of other oils and polymeric materials.
As used herein, "tumor cells" or "tumor" refers to an aggregate of abnormal cells and/or tissue which may be associated with diseased states that are characterized by uncontrolled cell proliferation. The disease states may involve a variety of cell types, including, for example, endothelial, epithelial and myocardial cells. Included among the disease states are neoplasms, cancer, and leukemia.
Any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4 + (wherein X is Ci-C4 alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX4 + (wherein X is independently selected from H or a C]-C4 alkyl group). For therapeutic use, salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention. COMPOUNDS OF THE INVENTION AND VARIANTS THEREOF One embodiment provides a compound of formula (XX):
Figure imgf000048_0001
(XX) wherein
X1 is Cό-C^alkylcarbonyl;
X2 is any amino acid or absent or
X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2-cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid, such as a nonpolar amino acid, or absent;
X6 is absent or at least one amino acid, such as a nonpolar amino acid;
R is independently at each occurrence H or (Ci-C6)alkyl;
R1 and R2 are independently (Ci-C4)alkyl or R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY1, NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group; R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C,o)alkenyl, (C2-C ,0)alkynyl, (C,-C,0)haloalkyl, (C3-C, 0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (C,- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB2, (C,-C6)haloalkyl, (Ci-Cό)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, wherein each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-
C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (CrC6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C(-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof.
In one embodiment, X1 is myristoyl or palmitoyl. In another embodiment, X2 is cysteine.
In one embodiment R1 and R2 are methyl; or one of R1 and R2 is methyl and the other is H.
In one embodiment, R3 is OMe.
In one embodiment, X2-X6 can be absent or any number of O, S, CR, NR or any substituted or unsubstituted amino acid.
In one embodiment, X3 is not Ala. In another embodiment, X4 is not VaI. In another embodiment, X5 is not Ala. In one embodiment, X3 is not Ala, X4 is not VaI and X5 is not Ala.
A compound of formula (XX) may have the following structure and characteristics:
(N-terminal end) (C-terminal end)
Myristoyl-Cys-Ala-Val-Ala-Tyr-(1,3 dimethyl)His-OMe (I)
Figure imgf000050_0001
Molecular Weight: 916.2 daltons Molecular Formula: C46H7SN8OgS+
Alternatively, the compound may have the following structure and characteristics: (N-terminal end) (C-terminal end)
Myristoyl-Cys-Ala-Val-Ala-Tyr-β methyOHis-OMe
Molecular Weight: 902.2 daltons Molecular Formula: C4SH73N8OgS+
This chemical structure is a natural product isolated and purified from Heliothis virescens insect hemolymph (blood) that has essentially none or very low cytotoxicity against human foreskin fibroblast cells. Generally, a natural product is designed by nature to kill something else and not the host cell itself. This is an important characteristic of the compound if used as a medicinal drug. A compound cannot be too cytotoxic to host cells if it is to be used as a beneficial drug to treat disease.
The N-terminal end of the compound of formula (I) is lipophilic and it is believed that its general function is to get the compound across and through the cell membrane. The positively charged C-terminal end, with its ring-shaped structure, which contains a histidine with two methyl groups (L-histidine, 1 ,3-dimethyl, methyl ester (not before found in nature)), is believed to inhibit DNA synthesis. Additionally, the imidazole ring of the histidine can have anti-helminthic, anti-fungal, anti-viral, anti-microbial, antibacterial, anti-protozoan, and/or insecticidal activity.
As discussed in detail below, anti-cancer activity was demonstrated against 34 different cancer cell tissue cultures (representing eight major human tumor types) and anti-viral activity against, for example, the Epstein-Barr Virus (EBV), human immunodeficiency virus (HIV), herpes simplex viruses 1 and 2, vesicular stomatitis virus (VSV), parainfluenxa-3, coxsackie B3 and sindbus virus. Several viruses have been demonstrated to cause cancer. For example, the Epstein-Barr Virus is described as a cancer-promoting double-stranded DNA virus (Thompson, M. P., Kurzrock, R. Clin. Cancer Res. 10, 803-821 , 2004). Antiviral drugs (like Acyclovir and Ganciclovir) are purine analogues and have ring-shaped purine structures as their active sites which inhibit DNA synthesis. The nitrogen-containing purine base has a double-ringed structure. The anti-tumor and antiviral compounds of the instant invention have at least one purine-like ring along with other rings at its C-terminal end. Generally, the compound contains six methyl groups (- CH3); however, this is not an absolute number and the compounds may be generated with more or fewer methyl groups (e.g., 1 , 2, 3, 4, 5, 7, 8, 9, 10 etc). Generally, it is believed that methyl groups are needed for rigidity of a compound and for good biological activity. Further, it is believed that methyl groups increase metabolic life, but also decrease the absorbance of a compound through the cell membrane. ENHANCED ENTRY INTO CELLS AND CELL TARGETING
Modification of the N-terminal end of the instant compound can enhance passage of the compound across and through the cell membrane in order to increase its concentration in the cell, and thus, effectiveness and biological activity inside the cell. ... Along with enhanced entry into a cell of interest, the compound can be altered in order to target a specific cell type. For example, acute myeloid leukemia is the most common adult leukemia and is also a childhood leukemia. Acute myeloid leukemia affects various white blood cells including granulocytes (70% of which are neutrophils), '""monocytes and platelets. Neutrophils and monocytes both express Toll-like receptor 2. Pam 2-cysteine and Pam 3-cysteine are lipid moieties that can specifically bind to Toll- like receptor 2. When the anti-tumor compounds described herein are linked to Pam 2- cysteine or Pam 3-cysteine at the N-terminal end, then the anti-tumor compounds are specifically targeted for entry into leukemic tumor cells. This mechanism of action can also be effective for acute myeloid leukemia when myristic acid is replaced by palmitic acid at the N-terminal end as is described below. This treatment approach can further be applicable for treatment of chronic myeloid leukemia. The anti-tumor compound described herein was very effective in vitro against all five of the five different leukemia cell tissue cultures tested by the National Cancer Institute (discussed in detail below). Example of N-terminal modification are presented below. In addition to these examples, any agent that aids in cell targeting and entry of the compounds can be used in the compounds, compositions and method of the instant invention. For example, the compounds of the invention can be synthesized to incorporate a cell targeting agent (e.g., any material or substance which may promote targeting of tissues, cells and/or receptors in vivo and/or in vitro of the compounds/compositions of the present invention), which can include, but is not limited to, peptides or proteins such as antibodies, including monoclonal and polyclonal (e.g., anti-CD20 antibody, anti-IL-2Rα antibody) and fragments thereof, ligands, including receptor ligands/proteins (preferably those that specifically bind to their receptors), peptides, polypeptides (e.g., Type I interferon, Type II interferon), cytokines (e.g., interleukin-1 ("IL-I "), interleukin-2 ("IL-2"), interleukin-3 ("IL-3"), interleukin-4 ("IL-4"), interleukin-5 ("IL-5"), interleukin-6 ("IL-6"), Interleukin-7 ("IL-7"), interleukin-8 ("IL-8"), Interleukin-10 ("IL-IO"), Interleukin-1 1 ("IL-I l "), interleukin-12 ("IL-12"), interleukin-13 ("IL-13") and tumor necrosis factor, growth factors (e.g., epidermal growth factor (EGF), transforming growth factor-β, vascular epithelial growth factor ("VEGF"), transforming growth factor-alpha or fragments thereof, vitamins and vitamin analogues such as folate, vitamin-B12, vitamin B6, niacin, nicotinamide, vitamin A and retinoid derivatives, ferritin and vitamin D, sugar molecules (e.g., glucose and glycogen) and polysaccharides, glycopeptides and glycoproteins, phospholipids, steroids, steroid analogs, hormones, cofactors, bioactive agents, and genetic material, including nucleosides, nucleotides and polynucleotides and drug molecules such as cyclosporin-A, prostaglandin or prostacyclin. Exemplary N-terminal Modifications
1) Myristoyl (Ci4 fatty acid) can be replaced with palmitoyl (Ci6 fatty acid). The - SH group of cysteine can be active in forming disulfide bond dimers of the compound. The dimer form of the compound can enhance its movement across the cell membrane and also increase its biological activity. Myristoyl is a C)4 fatty acid found in insect cell membranes, not in mammalian cell membranes. Palmitoyl is a C)6 fatty acid found in mammalian cell membranes. Substituting palmitoyl for myristoyl will make the fatty acid two carbons longer and can facilitate transfer of the compound across and through the mammalian cell membrane. This will increase concentration of the compound inside the cell, thus increasing cytoplasmic and nuclear effectiveness of the drug. (N-terminal end) (C-terminal end)
Palmitoyl-Cys-Ala-Val-Ala-Tyr-(1,3 dimethyl)His-OMe (II).
Molecular Weight: 944.3 Molecular Formula: C48HVgN8OgS+
2) Myristoyl (Ci4 fatty acid) can be replaced with palmitoyl (Ci6 fatty acid). Block the -SH group of cysteine by, for example, methylation (adding -CH3 group) so that dimerization of the compound with a disulfide bond (-S-S-) does not occur (chemical protecting/blocking groups and strategies for protection/deprotection are well known in the art. See e.g.. Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991).
(N-terminal end) (C-terminal end)
Palmitoyl-Cys-Ala-Val-Ala-Tyr-(1,3 dimethyl)His-OMe (III).
Molecular Weight: 958.3 Molecular Formula: C49H8iN8OgS+
3) Myristoyl (Ci4 fatty acid) can be replaced with palmitoyl (Ci6 fatty acid). Then synthesize as a dimer with a disulfide bond and use the oxidized product. Two palmitic acids would then be present and this can enhance even more passage of the compound across the cell membrane along with its having two C-terminal ends for increased biological activity.
(N-terminal end) (C-terminal end)
Palmitoyl-Cys-Ala-Val-Ala-Tyr-(1,3 dimethyl)His-OMe (Synthesize as a Dimer) (IV). Molecular Weight: 1886.5 (Dimer)
Molecular Formula: Cg6Hi56Ni6Oi8S2++
4) Both myristoyl (Q4 fatty acid) and cysteine can be replaced with Dipalmitoyl- S-glyceryl-cysteine (Pam 2-cysteine). No disulfide bond dimer can be formed here. (N-terminal end) (C-terminal end)
Dipalmitoyl-S-glyceryl-Cys-Ala-Val-Ala-Tyr-(l,3 dimethyl)His-OMe (V) Molecular Weight: 1 ,269.8 Molecular Formula: C68Hn6N8Oi2S+
5) Both myristoyl (Ci4 fatty acid) and cysteine can be replaced with Tripalmitoyl- S-glyceryl-cysteine (Pam 3-cysteine). No disulfide bond dimer can be formed here.
(N-terminal end) (C-terminal end)
Tripalmitoyl-S-glyceryl-Cys-Ala-Val-Ala-Tyr-Cl^ dimethyOHis-OMe (VI) Molecular Weight: 1 ,509.2 Molecular Formula: C84Hi47N8Oi3S+
Further modifications to the N-terminal end to increase transport of the compound across the cell membrane and/or target the compounds to a selected cell type, include, but are not limited to: replace myristic acid at N-terminal end with a Transporter Peptide Sequence (these are short basic peptide sequences that promote translocation across cell membranes, perhaps by endocytosis; examples are as follows: Console, S. et al., Antennapedia and HIV-Transactivator of Transcription (TAT) 'protein transduction domains' promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans. J. Biol. Chem. 278, 35109-351 14, 2003)); replace myristic acid with the HIV-TAT peptide sequence (a cell membrane permeable transport peptide); replace myristic acid with the Drosophila Antennapedia peptide sequence that is used for transport and delivery of plasmid DNA across lipid bilayers; or replace myristic acid at N-terminal end with various steroids (including, but not limited to, cholesterol, vitamin A, vitamin D, or other terpenoid lipids), to enhance passage of the compound across the cell membrane.
Other modification of the N-Terminal end to prevent dimerization of the compound, if needed, include, but are not limited to: use an amino acid that has similar characteristics as the amino acid it is replacing. For example, replace cysteine with serine, which has the same electrophilic properties (O vs. S) as cysteine or replace cysteine with homoalanine (ABU), which has the same chain length as cysteine. Other amino acid substitutions, including conservative amino acid substitutions, throughout the molecule are also encompassed by the instant invention. For example, the middle amino acid sequence Ala-Val-Ala of the compound can be substituted with non- polar amino acids or lengthened with non-polar amino acids. SCREENS FOR VIRAL INFECTION INHIBITORS AND CANCER INHIBITORS
Screens for Viral Infection Inhibitors
Compositions of the invention are screened for inhibitory activity against viruses by any of the conventional techniques for evaluating such activity (e.g., in vitro formazan assay for HlV-I anti-viral activity). Within the context of the invention, typically compositions are first screened for inhibition of infection in vitro and compositions showing inhibitory activity are then screened for activity in vivo. Compositions having in vitro Ki (inhibitory constants) of less then about 5 X 10~6 M, typically less than about 1
X 10~7 M and preferably less than about 5 X 10"^ M are preferred for in vivo use.
Useful in vitro screens have been described in detail and will not be elaborated here. However, the examples describe suitable in vitro assays. Screens for Cancer Inhibitors
Compositions of the invention are screened for activity against cancer by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for activity against cancer in vitro and compositions showing activity are then screened for activity in vivo. Useful in vitro screens have been described in detail and will not be elaborated here. However, the examples describe suitable in vitro assays. MECHANISM OF ACTION OF THE COMPOUNDS OF THE INVENTION
One skill in the art is to ascertain a mechanism of action for the compound from the in vitro assays used to determine the compounds biological activity. The in vitro assays used to determine anti-Epstein-Barr Virus (EBV) activity and anti-cancer activity inhibit DNA synthesis/replication, cell growth and cell division. The compound of interest inhibited DNA synthesis/replication of EBV in Akata cells (B-lymphocytes) in in vitro tissue culture. The effect of the compound on cancer cell growth was growth inhibition (inhibition of cell division occurring during the cell growth cycle) of cancer cells in in vitro tissue culture. From the in vitro assays used to determine biological activity, the compound inhibits then DNA synthesis/replication of the EBV and growth inhibition (inhibition of cell division) of cancer cells. The National Cancer Institute finds that their in vitro screen is an effective selector of compounds with in vivo anti-cancer and anti-viral activity. VIRUSES
The compounds, compositions and methods of this invention are useful in the treatment of a variety of RNA and DNA viruses. Treatment of viruses by the compounds of the invention include, but are not limited to, Abelson leukemia virus, Abelson murine leukemia virus, Abelson's virus, acute laryngotracheobronchitis virus, Adelaide River virus, adeno associated virus group, Adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, Aleutian mink disease parvovirus, alfalfa mosaic virus, alpharetrovirus, Alphavirus, ALV related virus, Amapari virus, Andean potato mottle virus, Aphthovirus, Aquareovirus, arbovirus, arbovirus C, arbovirus group A, arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus, Argentinean hemorrhagic fever virus, Arterivirus, Astrovirus, Ateline herpesvirus group, Aujezky's disease virus, Aura virus, Ausduk disease virus, Australian bat lyssavirus, Aviadenovirus, avian erythroblastosis virus, avian infectious bronchitis virus, avian leukemia virus, avian leukosis virus, avian lymphomatosis virus, avian myeloblastosis virus, avian paramyxovirus, avian pneumoencephalitis virus, avian reticuloendotheliosis virus, avian sarcoma virus, avian type C retrovirus group, Avihepadnavirus, B virus, Bl 9 virus, Babanki virus, baboon herpesvirus, bacterial virus, baculovirus, barley yellow dwarf virus, Barmah Forest virus, bean pod mottle virus, bean rugose mosaic virus, Bebaru virus, Berrimah virus, betaretrovirus, Birnavirus, Bittner virus, BK virus, Black Creek Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus, Boma disease virus, border disease of sheep virus, borna virus, bovine alphaherpesvirus 1, bovine alphaherpesvirus 2, bovine coronavirus, bovine ephemeral fever virus, bovine immunodeficiency virus, bovine leukemia virus, bovine leukosis virus, bovine mammillitis virus, bovine papillomavirus, bovine papular stomatitis virus, bovine parvovirus, bovine syncytial virus, bovine type C oncovirus, bovine viral diarrhea virus, bracovirus, broad bean mottle virus, broad bean stain virus, brome mosaic virus, Bromovirus, Buggy Creek virus, bullet shaped virus group, Bunyamwera virus supergroup, Bunyavirus, Burkitt's lymphoma virus, Bwamba Fever, Bwattany hetero virus, CA virus, Calicivirus, California encephalitis virus, camelpox virus, canarypox virus, canid herpesvirus, canine coronavirus, canine distemper virus, canine herpesvirus, canine minute virus, canine parvovirus, Cano Delgadito virus, Capillovirus, caprine arthritis virus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus, Cardiovirus, Carlavirus, Carmovirus, carrot mottle virus, Cassia yellow blotch virus, Caulimovirus, Cauliflower mosaic virus, caviid herpesvirus 1 , Cercopithecine herpesvirus 1 , Cercopithecine herpesvirus 2, cereal yellow dwarf virus, Chandipura virus, Changuinola virus, channel catfish virus, Charleville virus, chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, chub reovirus, chum salmon virus,
Closterovirus, Cocal virus, Coho salmon reovirus, coital exanthema virus, Colorado tick fever virus, Coltivirus, Columbia SK virus, Commelina yellow mottle virus, common cold virus, Comovirus, congenital cytomegalovirus, contagious ecthyma virus, contagious pustular dermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpea chlorotic mottle virus, cowpea mosaic virus, cowpea virus, cowpox virus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus), cricket paralysis virus, Crimean-Congo hemorrhagic fever virus, croup associated virus, Crypotovirus, Cucumovirus, Cypovirus, cytomegalovirus, cytomegalovirus group, cytoplasmic polyhedrosis virus, deer papillomavirus, defective virus, deltaretrovirus, Dengue, Densovirus, Dependovirus, Dhori virus, Dianthovirus, diploma virus, DNA virus, Drosophila C virus, duck hepatitis B virus, duck hepatitis virus 1, duck hepatitis virus 2, duovirus, Duvenhage virus, Deformed wing virus DWV, eastern equine encephalitis virus, eastern equine encephalomyelitis virus, EB virus, Ebola virus, Ebola-like virus, echo virus, echovirus, echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus, EIA virus, EMC virus, Emiliania huxleyi virus 86, encephalitis virus, encephalomyocarditis group virus, encephalomyocarditis virus, Enterovirus, enzyme elevating virus, enzyme elevating virus (LDH), epidemic hemorrhagic fever virus, epizootic hemorrhagic disease virus, Epstein- Barr virus, equid alphaherpesvirus 1 , equid alphaherpesvirus 4, equid herpesvirus 2, equine abortion virus, equine arteritis virus, equine encephalosis virus, equine infectious anemia virus, equine morbillivirus, equine rhinopneumonitis virus, equine rhinovirus, Eubenangu virus, European elk papillomavirus, European swine fever virus, Everglades virus, Eyach virus, Fabavirus, felid herpesvirus 1 , feline calicivirus, feline fibrosarcoma virus, feline herpesvirus, feline immunodeficiency virus, feline infectious peritonitis virus, feline leukemia /sarcoma virus, feline leukemia virus, feline panleukopenia virus, feline parvovirus, feline sarcoma virus, feline syncytial virus, Fijivirus, Filovirus, Flanders virus, Flavivirusfoot and mouth disease virus, Fort Morgan virus, Four Corners, hantavirus, fowl adenovirus 1 , fowlpox virus, Friend virus, Furovirus, gammaretrovirus, GB hepatitis virus, GB virus, Geminivirus, German measles virus, Getah virus, gibbon ape leukemia virus, green monkey virus (mullburg), glandular fever virus, goatpox virus, golden shinner virus, Gonometa virus, goose parvovirus, granulosis virus, Gross' virus, ground squirrel hepatitis B virus, group A arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pig type C virus, Hantaan virus, Hantavirus, hard clam reovirus, hare fibroma virus, HCMV (human cytomegalovirus), helper virus, hemadsorption virus 2, hemagglutinating virus of Japan, hemorrhagic fever virus, hendra virus, Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus group, hepatitis C virus, hepatitis D virus, hepatitis delta virus, hepatitis E virus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus, hepatitis virus, hepatitis virus (nonhuman), hepatoencephalomyelitis reovirus 3, Hepatovirus, heron hepatitis B virus, herpes B virus, herpes simplex virus, herpes simplex virus 1 , herpes simplex virus 2herpesvirus, herpes zoster, herpesvirus 7, Herpesvirus ateles, Herpesvirus hominis, Herpesvirus infection, Herpesvirus saimiri, Herpesvirus suis, Herpesvirus varicellae, Highlands J virus, Hirame rhabdovirus, hog cholera virus, Hordeivirus, human adenovirus 2, human alphaherpesvirus 1 , human alphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropic virus, human betaherpesvirus 5, human coronavirus, human foamy virus, human gammaherpesvirus 4, human gammaherpesvirus 6, human hepatitis A virus, human herpesvirus 1 group, human herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus 4 group, human herpesvirus 6, human herpesvirus 8, human immunodeficiency virus, human immunodeficiency virus 1 , human immunodeficiency virus 2, human papillomavirus, human T cell leukemia virus, human T cell leukemia virus I, human T cell leukemia virus II, human T cell leukemia virus III, human T cell lymphoma virus I, human T cell lymphoma virus II, human T cell lymphotropic virus type 1, human T cell lymphotropic virus type 2, human T lymphotropic virus I, human T lymphotropic virus II, human T lymphotropic virus III, ichnovirus, Ilarvirus, infantile gastroenteritis virus, infectious bovine rhinotracheitis virus, infectious haematopoietic necrosis virus, infectious pancreatic necrosis virus, influenza A virus, influenza B virus, influenza virus (unspecified), influenzavirus (unspecified), influenzavirus A, influenzavirus B, influenzavirus C, influenzavirus D, influenzavirus pr8, insect iridescent virus, insect virus, interfering virus, iridovirus, Japanese B virus, Japanese~encephalitis virus, JC virus, Junin virus, Johnson grass mosaic virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo virus, Kilham's rat virus, Klamath virus, Kolongo virus, Korean hemorrhagic fever virus, kumba virus, Kysanur forest disease virus, Kyzylagach virus, La Crosse virus, lactic dehydrogenase elevating virus, lactic dehydrogenase virus, Lagos bat virus, Lambda phage, Langur virus, lapine parvovirus, Lassa fever virus, Lassa virus, latent rat virus, LCM virus, Leaky virus, Lentivirus, Leporipoxvirus, leukemia virus, leukovirus, lumpy skin disease virus, Luteovirus, lymphadenopathy associated virus, Lymphocryptovirus, lymphocytic choriomeningitis virus, lymphoproliferative virus group, Lyssavirus, Machupo virus, mad itch virus, maize chlorotic dwarf virus, maize rough dwarf virus, mammalian type B oncovirus group, mammalian type B retroviruses, mammalian type C retrovirus group, mammalian type D retroviruses, mammary tumor virus, Mapuera virus, Marafivirus, Marburg virus, Marburg-like virus, Mason Pfizer, monkey virus, Mastadenovirus, Mayaro virus, ME virus, measles virus, Melandrium yellow fleck virus, Menangle virus, Mengo virus, Mengovirus, Middelburg virus, milkers nodule virus, mink enteritis virus, minute virus of mice, MLV related virus, MM virus. Mokola virus, Molluscipoxvirus, Molluscum contagiosum virus, monkey B virus, monkeypox virus, Mononegavirales, Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus, mouse K virus, mouse leukemia virus, mouse mammary tumor virus, mouse minute virus, mouse pneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosal disease virus, mumps virus, murid betaherpesvirus 1 , murid cytomegalovirus 2, murine cytomegalovirus group, murine encephalomyelitis virus, murine hepatitis virus, murine leukemia virus, murine, nodule inducing virus, murine polyomavirus, murine sarcoma virus, Muromegalovirus, Murray Valley encephalitis virus, myxoma virus, Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheep disease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus, Necrovirus, Neethling virus, Nelson Bay virus, Neopvirus, neurotropic virus, New World Arenavirus, newborn pneumonitis virus, Newcastle disease virus, Nipah virus, noncytopathogenic virus, Noravirus, Norwalk virus, nuclear polyhedrosis virus (NPV), nipple neck virus, O'nyong'nyong virus, oat sterile dwarf virus, Ockelbo virus, oncogenic virus, oncogenic viruslike particle, oncornavirus, Orbivirus, Orf virus, Oropouche virus, Orthohepadnavirus, orthomyxovirus, Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovine catarrhal fever virus, owl monkey herpesvirus, Palyam virus, Papillomavirus, Papillomavirus sylvilagi, Papovavirus, parainfluenza virus, parainfluenza virus type 1 , parainfluenza virus type 2, parainfluenza virus type 3, parainfluenza virus type 4, Paramyxovirus, Parapoxvirus, paravaccinia virus, parsnip yellow fleck virus, Parvovirus, Parvovirus B 19, parvovirus group, pea enation mosaic virus, Pestivirus, Phlebovirus, phocine distemper virus, Phytoreovirus, codnavirus, Picornavirus, pig cytomegalovirus, pigeonpox virus, Piry virus, Pixuna virus, plant rhabdovirus group, plant virus, pneumonia virus of mice, Pneumovirus, poliomyelitis virus, poliovirus, Polydnavirus, polyhedral virus, polyoma virus, Polyomavirus, Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2, Polyomavirus maccacae 1 , Polyomavirus muris 1 , Polyomavirus muris 2, Polyomavirus papionis 1 , Polyomavirus papionis 2, Polyomavirus sylvilagi, Pongine herpesvirus 1, porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, porcine parvovirus, porcine transmissible gastroenteritis virus, porcine type C virus, Potato leaf roll virus, Potato mop top virus, Potato virus Y, Potexvirus, Potyvirus, pox virus, poxvirus, poxvirus variolae, Prospect Hill virus, provirus, pseudocowpox virus, pseudorabies virus, psittacinepox virus, Puumala virus, Qalyub virus, Quail pea mosaic virus, quailpox virus, Queensland fruitfly virus, Quokkapox virus, rabbit fibroma virus, rabbit kidney vacuolating virus, rabbit papillomavirus, rabies virus, raccoon parvovirus, raccoonpox virus, radish mosaic virus, Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus, Rauscher's virus, recombinant vaccinia virus, recombinant virus, reovirus, reovirus 1 , reovirus 2, reovirus 3, reptilian type C virus, respiratory infection virus, respiratory syncytial virus, respiratory virus, reticuloendotheliosis virus,
Retrovirus, Rhabdovirus, Rhabdovirus carpia, Rhadinovirus, rhinovirus, Rhizidiovirus, rice dwarf virus, rice gall dwarf virus, rice hoja blanca virus, rice ragged stunt virus, Rift Valley fever virus, Riley's virus, rinderpest virus, RNA tumor virus, RNA virus, Ross River virus, Rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeola virus, Rubivirus, Russian autumn encephalitis virus, S6- 14-03 virus, SA 1 1 simian virus, SA 15, SA2 virus, SA6 virus, SA8 virus, Sabia virus, Sabio virus, Saboya virus, Sabulodes caberata GV, Sacbrood virus, Saccharomyces cerevisiae virus L-A, Saccharomyces cerevisiae virus La, Saccharomyces cerevisiae virus LBC, Sagiyama virus, Saguaro cactus virus, Saimiriine herpesvirus 1 , Saimiriine herpesvirus 2, Sainpaulia leaf necrosis virus, SaintAbb's Head virus, Saint-Floris virus, Sakhalin virus, Sal Vieja virus, Salanga virus, Salangapox virus, Salehabad virus, salivary gland virus, Salmonid herpesvirus 1 , Salmonid herpesvirus 2, Salmonis virus, Sambucus vein clearing virus, Samia cynthia NPV, Samia pryeri NPV, Samia ricini NPV, Sammons' Opuntia virus, SanAngelo virus, San Juan virus, San Miguel sealion virus, San Perlita virus, Sand rat nuclear inclusion agents, Sandfly fever Naples virus, Sandfly fever Sicilian virus, Sandjimba virus, Sango virus, Santa Rosa virus, Santarem virus, Santosai temperate virus, Sapphire II virus, Saraca virus, Sarracenia purpurea virus, SARS virus, satellite virus, Sathuperi virus, Satsuma dwarf virus, Saturnia pavonia virus, Saturnia pyri NPV, Saumarez Reef virus, Sawgrass virus, Sceliodes cordalis NPV, Schefflera ringspot virus, Sciaphila duplex GV, Scirpophaga incertulas NPV, Sciurid herpesvirus, Sciurid herpesvirus 2, Scoliopteryx libatFix NPV, Scopelodes contracta NPV, Scopelodes venosa NPV, Scopula subpunctaria NPV, Scotogramma trifolii GV, Scotogramma trifolu NPV, Scrophularia mottle virus, SDAV (sialodacryoadenitis virus), sealpox virus, Selenephera lunigera NPV, Selepa celtis GV, Seletar virus, Selidosema suavis NPV, Semidonta biloba NPV, Semiothisa sexmaculata GV, Semliki Forest Virus, Semliki Forest virus, Sena Madureira virus, Sendai virus, Seoul virus, Sepik virus, rra do Navio virus, Serrano golden mosaic virus, Sesame yellow mosaic virus, Sesamia calamistis NPV, Sesamia cretica GV, Sesamia inferens NPV, Sesamia nonagrioides GV, Setora nitens virus, Shallot latent virus, Shamonda virus, Shark River virus, Sheep associated malignant catarrhal fever, Sheep papillomavirus, Sheep pulmonary adenomatosis associated herpesvirus, sheeppox virus, Shiant Islands virus, Shokwe virus, Shope fibroma virus, Shope papilloma virus, Shuni virus, Siamese cobra herpesvirus, Sibine fusca densovirus, Sida golden mosaic virus (SiGMV), Sida golden yellow vein virus (SiGYVV), Sigma virus, Sikte water-borne virus, Silverwater virus, Simbu virus, Simian adenoviruses 1 to 27, Simian agent virus 12, Simian enterovirus 1 to 18, simian foamy virus, Simian hemorrhagic fever virus, simian hepatitis A virus, simian human immunodeficiency virus, simian immunodeficiency virus, simian parainfluenza virus, Simian rotavirus SAl 1 , Simian sarcoma virus, simian T cell lymphotrophic virus, Simian type D virus 1 , Simian vancella herpesvirus, simian virus, simian virus 40, Simplexvirus, Simulium vittatum densovirus, Sin Nombre virus, Sindbis virus, Sintl em's onion latent virus, Sixgun city virus, Skunkpox virus, smallpox virus, Smelt reovirus, Smerinthus ocellata NPV, Smithiantha virus, Snakehead rhabdovirus, Snowshoe hare virus, Snyder-Theilen feline sarcoma virus, Sobemovirus, Sofyn virus, Soil-borne wheat mosaic virus, Sokoluk virus, Solanum apical leaf curl virus, Solanum nodiflorum mottle virus, Solanum nodiflorum mottle virus satellite, Solanurn yellows virus, Soldado virus, Somerville virus 4, Sonchus mottle virus, Sonchus virus, Sonchus yellow net virus, Sorghum chlorotic spot virus, Sorghum mosaic virus, Sorghum virus, Sororoca virus, Soursop yellow blotch virus, South African passiflora virus, South American hemorrhagic fever viruses, South African passiflora virus, South River virus, Southern bean mosaic virus, Southern potato latent virus, Sowbane mosaic virus, Sowthistle yellow vein virus, Soybean chlorotic mottle virus, Soybean crinkle leaf virus, Soybean dwarf virus, Soybean mosaic virus, SPAr-2317 virus, Sparganothis pettitana NPV, sparrowpox virus, Spartina mottle virus, Spectacled caimanpox virus, SPH 1 14202 virus, Sphenicid herpesvirus 1, Sphinx ligustri NPV, Spider monkey herpesvirus, Spilarctia subcarnea NPV, Spilonota ocellana NPV, Spilosoma lubricipeda NPV, Spinach latent virus, Spinach temperate virus, Spiroplasma phage 1, Spiroplasma phage 4, Spiroplasma phage aa, Spiroplasma phage Cl /TS2, Spodoptera exempta cypovirus 1 1, Spodoptera exempta cypovirus 12, Spodoptera exemptacypovirus 3, Spodoptera exempta cypovirus 5, Spodoptera exempta cypovirus 8, Spodoptera exempta NPV, Spodoptera exigua cypovirus 1 1, Spodoptera exigua GV, Spodoptera exigua MNPV, Spodoptera exigua NPV, Spodoptera frugiperda GV, Spodoptera frugiperda MNPV, Spodoptera frugiperda NPV, Spodoptera latifascia NPV, Spodoptera littoralis, Spodoptera littoralis NPV, Spodoptera litura GV, Spodoptera litura NPV, Spodoptera mauritia NPV, Spodoptera ornithogalli NPV, Spondweni virus, spring beauty latent virus, Spring viremia of carp virus, Spumavirus, Squash leaf curl virus, squash mosaic virus, squirrel fibroma virus, Squirrel monkey herpesvirus, squirrel monkey retrovirus, SR-1 1 virus, Sri Lankan passionfruit mottle virus, Sripur virus, SSV 1 virus group, StAbbs Head virus, St. Louis encephalitis virus, Staphylococcus phage 107, Staphylococcus phage 187, Staphylococcus phage 2848A, Staphylococcus phage 3A, Staphylococcus phage 44A HJD, Staphylococcus phage 77, Staphylococcus phage BI l - M 15, Staphylococcus phage Twort, Starlingpox virus, Statice virus Y, P, STLV (simian T lymphotropic virus) type I, STLV (simian T lymphotropic virus) type II, STLV (simian T lymphotropic virus) type III, stomatitis papulosa virus, Stratford virus, Strawberry crinkle virus, Strawberry latent ringspot virus, Strawberry latent ringspot virus satellite, Strawberry mild yellow edge virus, Strawberry mild yellow edge-associated virus, Strawberry pseudo mild yellow edge virus, Strawberry vein banding virus, Streptococcus phage 182, Streptococcus phage 2BV, Streptococcus phage A25, Streptococcus phage 24, Streptococcus phage PEl, Streptococcus phage VD 13, Streptococcus phage fD8, Streptococcus phage CP-I , Streptococcus phage Cvir, Streptococcus phage H39, Strigid herpesvirus 1 , Striped bass reovirus, Striped Jack nervous necrosis virus, Stump-tailed macaque virus, submaxillary virus, Subterranean clover mottle virus, Subterranean clover mottle virus satellite, Subterranean clover red leaf virus, Subterranean clover stunt virus, Sugarcane bacilliform virus, Sugarcane mild mosaic virus, Sugarcane mosaic virus, Sugarcane streak virus, suid alphaherpesvirus 1 , suid herpesvirus 2, Suipoxvirus,
Sulfolobus virus 1, Sunday Canyon virus, Sunflower crinkle virus, Sunflower mosaic virus, Sunflower rugose mosaic virus, Sunflower yellow blotch virus, Sunflower yellow ringspot virus, Sun-hemp mosaic virus, swamp fever virus, Sweet clover necrotic mosaic virus, Sweet potato A virus, Sweet potato chlorotic leafspot virus, Sweet potato feathery mottle virus, Sweet potato internal cork virus, Sweet potato latent virus, Sweet potato mild mottle virus, Sweet potato russet crack virus, Sweet potato vein mosaic virus, Sweet potato yellow dwarf virus, Sweetwater Branch virus, Swine cytomegalovirus, Swine infertility and respiratory syndrome virus, swinepox virus, Swiss mouse leukemia virus, Sword bean distortion mosaic virus, Synaxis jubararia NPV, Synaxis pallulata NPV, Synetaeris tenuifemur virus, Syngrapha selecta NPV, T4 phage, T7 phage, TAC virus, Tacaiuma virus, Tacaribe complex virus, Tacaribe virus, Tadpole edema virus LT 1-4, Taggert virus, Tahyna virus, Tai virus, Taiassui virus, Tamana bat virus, Tamarillo mosaic virus, Tamdy virus, Tamiami virus, Tanapox virus, Tanga virus, Tanjong Rabok virus, Taro bacilliform virus, Badnavirus Tataguine virus, Taterapox virus, Taterapox virus, Poxviridae, Teasel mosaic virus, Tehran virus, Telfairia mosaic virus, Telok Forest virus, Tembe virus, Tembusu virus, Tench reovirus, Tensaw virus, Tenvivirus, Tephrosia symptomless virus, Termeil virus, Tete virus, Tetralopha scortealis NPV, Tetropium cinnamoptemm NPV, Texas pepper virus, Thailand virus, Thaumetopoea pityocampa GV, Thaumetopoea pityocampa NPV, Thaumetopoea processionea NPV, Theiler's encephalomyelitis virus, Theiler's virus, Theophila mandarina NPV, Theretra japonica NPV, Thermoproteus virus 1 , Thermoproteus virus 2, Thermoproteus virus 3,
Thermoproteus virus 4, Thiafora virus, Thimiri virus, Thistle mottle virus, Thogoto virus, Thormodseyjarklettur virus, Thosea asigna virus, Thosea baibarana NPV, Thosea sinensis GV, Thottapalayam virus, Thylidolpteryx ephemeraeformis NPV, Thymelicus lineola NPV, Tibrogargan virus, Ticera castanea NPV, Tick borne encephalitis virus, Tillamook virus, Tilligerry virus, Timbo virus, Tilmboteua virus, Tilmaroo virus, Tindholmur virus, Tinea pellionella NPV, Tineola hisselliella NPV, Tinpula paludosa NPV, Tinracola plagiata NPV, Tioman virus, Tlacotalpan virus, Tobacco bushy top virus, Tobacco etch virus, Tobacco leaf curl virus, Tobacco mild green mosaic virus, tobacco mosaic virus, Tobacco mosaic virus satellite, Tobacco mottle virus, Tobacco necrosis virus, Tobacco necrosis virus satellite, Tobacco necrosis virus small satellite, Tobacco necrotic dwarf virus, tobacco rattle virus, Tobacco ringspot virus, Tobacco ringspot virus satellite, Tobacco streak virus, Tobacco stunt virus, Tobacco vein banding mosaic virus, Tobacco vein distorting virus, Tobacco vein mottling virus, Tobacco wilt virus, Tobacco yellow dwarf virus, Tobacco yellow net virus, Tobacco yellow vein assistor virus, Tobacco yellow vein virus, Tobamovirus, Tobravirus, Togavirus, Tomato apical stunt viroid, Tomato aspermy virus, Tomato black ring virus, Tomato black ring virus satellite, Tomato bunchy top viroid, tomato bushy stunt virus, Tomato bushy stunt virus satellite, Tomato golden mosaic virus, Tomato leaf crumple virus, Tomato leaf curl virus-Au, Tomato leaf curl virus-In, Tomato leafroll virus, Tomato mosaic virus, Tomato mottle virus, Tomato pale chlorosis virus, Tomato planta macho viroid, Tomato pseudo-curly top virus, Tomato ringspot virus, Tomato spotted wilt virus, Tomato top necrosis virus, Tomato vein yellowing virus, Tomato yellow dwarf virus, Tomato yellow leaf curl virus- Is, Tomato yellow leaf curl virus-Sr, Tomato yellow leaf curl virus-Th, Tomato yellow leaf curl virus- Ye, Tomato yellow mosaic virus, Tomato yellow top virus, Tombusvirus, Tongan vanilla virus, Torovirus, Tortrix loeflingiana NPV, Tortrix viridana NPV, Toscana virus, Tospovirus, Toxorhynchites brevipalpis NPV, Trabala vishnou NPV, Tradescantia/Zebrina virus, Trager duck spleen necrosis virus, Tranosema sp. Virus, transforming virus, Tree shrew adenovirus 1 , tree shrew herpesvirus, Triatoma virus, Tribec virus, Trichiocampus irregularis NPV, Trichiocampus viminalis NPV, Trichomonas vaginalis virus, Trichoplusia ni cypovirus 5, Trichoplusia ni granulovirus, Trichoplusia ni MNPV, Trichoplusia ni Single SNPV, Trichoplusia ni virus,
Trichosanthes mottle virus, Triticum aestivum chlorotic spot virus, Trivittatus virus, Trombetas virus, Tropaeolum virus 1 , Uasin Gishu disease virus, Uganda S virus, Ugymyia sericariae NPV, ulcerative disease rhabdovirus, Ullucus mild mottle virus, Ullucus mosaic virus, Ullucus virus C, Umatilla virus, Umbre virus, Una virus, Upolu virus, UR2 sarcoma virus, Uranotaenia sapphirina NPV, Urbanus proteus NPV, Urucuri virus, Ustilago maydis virus 1 , Ustilago maydis virus 4, Ustilago maydis virus 6, Usutu virus, Utinga virus, Utive virus, Uukuniemi virus group, vaccinia virus, Vaeroy virus, Vallota mosaic virus, Vanessa atalanta NPV, Vanessa cardui NPV, Vanessa prorsa NPV, Vanilla mosaic virus, Vanilla necrosis virus, varicella zoster virus, Varicellovirus, Varicola virus, variola major virus, variola virus, Vasin Gishu disease virus, Vellore virus, Velvet tobacco mottle virus, Velvet tobacco mottle virus satellite, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagic fever virus, Vesicular stomatitis Alagoas virus, Vesicular stomatitis Indiana virus, Vesicular stomatitis New Jersey virus, Vesicular stomatitis virus, Vesiculovirus, Vicia cryptic virus, Vigna sinensis mosaic virusm, Vilyuisk virus, Vinces virus, Viola mottle virus, viper retrovirus, viral haemorrhagic septicemia virus, virus-like particle, Visna Maedi virus, Visna virus, Voandzeia mosaic virus, Voandzeia necrotic mosaic virus, volepox virus, Wad Medani virus, Wallal virus, Walleye epidermal hyperplasia, Walrus calicivirus, Wanowrie virus, Warrego virus, Watermelon chlorotic stunt virus, Watermelon curly mottle virus, Watermelon mosaic virus 1 , Watermelon mosaic virus 2, Weddel water-borne virus, Weldona virus, Wesselsbron virus, West Nile virus, western equine encephalitis virus, western equine encephalomyelitis virus, Wexford virus, Whataroa virus, Wheat American striate mosaic virus, wheat chlorotic streak virus, Wheat dwarf virus, Wheat rosette stunt virus, Wheat spindle streak mosaic virus, Wheat streak mosaic virus, Wheat yellow leaf virus, Wheat yellow mosaic virus, white bryony mosaic virus, White bryony virus, White clover cryptic virus 1 , White clover cryptic virus 2, White clover cryptic virus 3, White clover mosaic virus, White lupinrnosaic virus, Wild cucumber mosaic virus, Wild potato mosaic virus, Wildbeest herpesvirus, Wineberry latent virus, Winter wheat mosaic virus, Winter wheat Russian mosaic virus, Wiseana cervinata GV, Wiseana cervinata NPV, Wiseana signata NPV, Wiseana umbraculata GV, Wiseana umbraculata NPV, Wissadula mosaic virus, Wisteria vein mosaic virus, Witwatersrand virus, Wongal virus, Wongorr virus, Winter Vomiting Virus, woodchuck hepatitis B virus, Woodchuck herpesvirus marmota 1 , woolly monkey sarcoma virus, wound tumor virus, WRSV virus, WVU virus 2937, WW virus 71 to 212, Wyeomyia smithii NPV, Wyeomyia virus, Xenopus virus T21 , Xiburema virus, Xingu virus, Xylena curvimacula NPV, Y73 sarcoma virus, Yaba monkey tumor virus, Yaba-1 virus, Yaba-7 virus, Yacaaba virus, Yam mosaic virus, Yaounde virus, Yaquina Head virus, Yatapoxvirus, yellow fever virus, Yogue virus, Yokapox virus, Yokase virus, Yponomeuta cognatella NPV, Yponomeuta evonymella NPV, Yponomeuta malinellus NPV, Yponomeuta padella NPV, Yucca baciliform virus, Yug Bogdanovac virus, Zaliv_ Terpeniya virus, Zea mays virus, Zegla virus, Zeiraphera diniana GV, Zeiraphera diniana NPV, Zeiraphera pseudotsugana NPV, Zika virus, Zirqa virus, Zoysia mosaic virus, Zucchini yellow fleck virus, Zucchini yellow mosaic virus and/or Zygocactus virus.
For example, treatment of viruses/viral infections by the compounds of the invention include, but are not limited to, HIV, herpes simplex virus-1 (HSV-I), herpes simplex virus-2 (HSV-2), vesicular stomatitis, parainfluenza-3, coxsackie B3, sindbis viruses and Epstein Barr viruses (EBV). In on embodiment, the treatment of viruses/viral infections does not include HIV or herpes simplex virus-1 (HSV-I).
In another embodiment, the treatment of viruses/viral infections does not include HIV, herpes simplex virus-1 (HSV-I), herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenzal, coxsackie B3, or sindbis viruses. In one embodiment, the treatment of viruses/viral infections includes Epstein Ban- virus (EBV).
The Epstein-Barr virus (EBV), also called Human herpesvirus 4 (HHV-4), is a virus of the herpes family (which includes Herpes simplex virus and Cytomegalovirus), and is one of the most common viruses in humans. Most people become infected with EBV, which is often asymptomatic, but commonly causes infectious mononucleosis. EBV is also associated with various malignancies.
On infecting the B-lymphocyte, the EBV linear virus genome circularizes and the virus subsequently persists within the cell as an episome. The virus can execute several distinct programs of gene expression which can be broadly categorized as being the lytic cycle or latent cycle.
The lytic cycle or productive infection results in staged expression of a host of viral proteins with the ultimate objective of producing infectious virions. This phase of infection usually does not inevitably lead to lysis of the host cell as EBV virions are produced by budding from the infected cell.
The latent cycle (lysogenic) programs are those that do not result in production of virions. A very limited, distinct set of viral proteins are produced during the latent cycle infection. These include Epstein-Barr nuclear antigen (EBNA)-I, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-leader protein (EBNA-LP) and latent membrane proteins (LMP)- 1 , LMP-2A and LMP-2B and the Epstein-Barr encoded RNAs (EBERs). In addition, EBV codes for at least twenty microRNAs which are expressed in latently infected cells.
From studies of EBV gene expression in cultured Burkitt's lymphoma cell lines, at least three programs exist: EBNA l only (group I); EBNA l + EBNA2 (group II); and Latent cycle proteins (group III). It is also postulated that a program in which all viral protein expression is shut off exists.
When EBV infects B-lymphocytes in vitro, lymphoblastoid cell lines eventually emerge that are capable of indefinite growth. The growth transformation of these cell lines is the consequence of viral protein expression. EBNA-2, EBNA-3C and LMP-I are believed to be needed for transformation, while EBNA-LP and the EBERs are not. The EBNA-I protein is generally believed to be needed for maintenance of the virus genome (Yates JL, et al. (1985) Nature 313: 812-5).
It is postulated that following natural infection with EBV, the virus executes some or all of its repertoire of gene expression programs to establish a persistent infection. Given the initial a"bsence of host immunity, the lytic cycle produces large amounts of virus to infect other (presumably) B-lymphocytes within the host.
The latent programs reprogram and subvert infected B-lymphocytes to proliferate and bring infected cells to the sites at which the virus presumably persists. Eventually, when host immunity develops, the virus persists by turning off most (or possibly all) of its genes, only occasionally reactivating to produce fresh virions. A balance is eventually struck between occasional viral reactivation and host immune surveillance removing cells that activate viral gene expression.
The site of persistence of EBV may be bone marrow. EBV-positive patients who have had their own bone marrow replaced with bone marrow from an EBV-negative donor are found to be EBV-negative after transplantation (Gratama JW, et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85: 8693-6).
All EBV nuclear proteins are produced by alternative splicing of a transcript starting at either the Cp or Wp promoters at the left end of the genome (in the conventional nomenclature). The genes are ordered EBNA-LP/EBNA-2/EBNA- 3A/EBNA-3B/EBNA-3C/EBNA-1 within the genome.
EBV microRNAs are encoded by two transcripts, one set in the BART gene and one set near the BHRFl cluster. The three BHRFl miRNAS are expressed during type III latency while the large cluster of BART miRNAs (up to 20 miRNAs) are expressed during type II latency. The functions of these miRNAs are currently unknown. Epstein-Barr can cause infectious mononucleosis, also known as "glandular fever," "Mono" and "Pfeiffer's disease." Infectious mononucleosis is caused when a person is first exposed to the virus, generally during or after adolescence. Though once deemed "The Kissing Disease," research has shown that transmission of Mono not only occurs from exchanging saliva, but also from contact with the airborne virus. It is predominantly found in the developed world, and most children in the developing world are found to have already been infected by around 18 months of age. EBV antibody tests turn up almost universally positive. In the United States up to 95% of adults between 35 and 40 years of age have been infected with EBV (National Center for Infectious Diseases).
EBV is also associated with various malignancies. The strongest evidence linking EBV and cancer formation is found in Burkitt's lymphoma and nasopharyngeal carcinoma. Burkitt's lymphoma is a type of Non-Hodgkin's lymphoma. Burkitt's lymphoma is common in equatorial Africa and is co-existent with the presence of malaria. Malaria infection causes reduced immune surveillance of EBV immortalized B cells, thus allowing their proliferation. This proliferation increases the chance of a mutation to occur. Repeated mutations can lead to the B cells escaping the body's cell- cycle control, thus allowing the cells to proliferate unchecked, resulting in the formation of Burkitt's lymphoma. Burkitt's lymphoma commonly affects the jaw bone, forming a huge tumor mass. It responds to chemotherapy treatment, namely cyclophosphamide, but recurrence is common. Other B cell lymphomas arise due to EBV in immuno-compromised patients such as those with AIDS or who have undergone organ transplantation with associated immunosuppression (Post-Transplant Lymphoproliferative Disorder (PTLPD)). Smooth muscle tumors are also associated with the virus in malignant patients.
Nasopharyngeal carcinoma is a cancer found in the upper respiratory tract, most commonly in the nasopharynx, and is linked to the EBV virus. It is found predominantly in Southern China and Africa, due to both genetic and environmental factors. It is much more common in people of Chinese ancestry (genetic), but is also linked to the Chinese diet of a high amount of smoked fish, which contain nitrosamines, well known carcinogens (environmental). Additionally, EBV has been postulated to be a trigger for a subset of chronic fatigue syndrome patients (Lerner AM, et al., (2004) In Vivo 18(2): 101 -6) as well as multiple sclerosis and other autoimmune diseases (Lϋnemann JD, and Mϋnz C (2007) Current neurology and neuroscience reports 7(3): 253-8).
Diseases associated with EBV include, but are not limited to, infectious mononucleosis; Stevens-Johnson syndrome; Hepatitis; Herpes; Alice in Wonderland syndrome; Several Non-Hodgkin's lymphomas, including primary cerebral lymphoma and Burkitt's lymphoma; lymphomas of immunosuppressed subjects (e.g., AIDS patients or transplant recipients); B-cell tumors, T-cell tumors; B lymphoproliferative disease; Hodgkin's lymphoma/disease; nasopharyngeal carcinoma; post-transplant lymphoproliferative disorder; herpangina; multiple sclerosis; Hairy leukoplakia; Common variable immunodeficiency (CVID) and Kikuchi's disease. No anti-viral therapies are currently in use with regards to treatment of these diseases/disorders. Currently, such patients are treated by only supportive treatment regimes. CANCERS (SOLID AND NON-SOLID)
The compounds, compositions and methods of this invention are also useful in the treatment of a variety of cancers (solid and non-solid) and tumors including, but not limited to tumors of the breast, bladder, cervix, colon, gall bladder, kidney, liver, lung, pancreas, ovary, prostate, skin, stomach, thyroid, and the like. In some embodiments the compositions of the invention can be used to inhibit, treat or prevent carcinomas such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; blood, hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma. In some embodiments, the invention can be used to inhibit, treat or prevent Non-Small Cell Lung Cancer, Colon Cancer, Breast Cancer, Ovarian Cancer, Leukemia, Renal Cancer, Melanoma, and/or CNS (Brain) Cancer. EXEMPLARY METHODS OF MAKING/ISOLATING THE COMPOUNDS OF THE INVENTION The invention also relates to methods of making and/or isolating the compounds/compositions of the invention. The compounds are prepared by any of the applicable techniques of organic synthesis available to the art. Many such techniques are well known in the art and are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1 , Ian T. Harrison and Shuyen Harrison, 1971 ; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis- Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing). Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100°C to 200°C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 0C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 °C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 °C to -100 0C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art and will be applied when applicable. The molecular structure of the insect anti-viral compound was synthesized by
Bachem Bioscience Inc., King of Prussia, PA. The structure Myristoyl-Cys-Ala-Val-Ala- Tyr-(3 methy I)His-OMe was synthesized. This synthesized structure was used to obtain the anti-EBV results, anti-cancer data and cytotoxicity assay results with human foreskin fibroblast cells presented herein.
Further, the compound of formula (I) can be isolated from the hemolymph of Heliothis virescens, as discussed in D. Ourth, Antiviral activity against human immunodeficiency virus- 1 in vitro by myristoylated-peptide from Heliothis virescens, Biochemical and Biophysical Research Communications, 320, 190-196, 2004. Briefly, the hemolymph (blood) was collected with capillary tubes from fifth-instar larvae under ice-chilling conditions. Cell-free hemolymph was obtained by centrifugation at 10,000 rpm for 10 min at 4°C. The hemolymph was stored at -80°C. The hemolymph was thawed at room temperature and then centrifuged at 10,000 rpm for 10 min at 4°C to separate the melanin precipitate. The melanin precipitate, after washing once with sterile water, was solubilized in 0.05 M phosphate buffered saline, pH 7.55, with vortexing. Following centrifugation, the supernatant was applied to a gel-filtration HPLC-column (described below).
Solubilized products of the insect melanization reaction were analyzed by high pressure liquid chromatography (HPLC) (ISCO Instrumentation, Lincoln, NE) to isolate and purify the hemolymph antiviral factor. Three major peaks and four minor peaks were seen when the solubilized melanin was applied to a low molecular weight Shodex KW- 802.5 gel-filtration (separation range 100-50,000 Da) HPLC column (Millipore, Milford, MA) in 0.2 sodium phosphate buffer, pH 7.0. One milliliter tube fractions of these peaks were collected. Three of the low molecular weight fractions (#12, #15, and #16) showed major anti-HIV-1 activity using the formazan assay. One of the three tube fractions (#16) showed greater antiviral activity against HIV-I and was further purified and separated by reverse-phase HPLC (C- 18 column, Rainin Instrument, Woburn, MA).
Elution of antiviral retention fractions by C- 18 reverse-phase HPLC was performed with a linear gradient of 0-50% acetonitrile in 0.1% trifluoroacetic acid (TFA) over a period of 50 min at a flow rate of 1 ml/min. The organic solvent acetonitrile/water (50/50 v/v) containing 0.1% TFA was used as the final concentration of eluant. Ultraviolet absorption was monitored at 280 nm. The eluted retention fractions were vacuum concentrated (Speed Vac, Savant, Farmingdale, NY) and then dissolved in 0.05 M phosphate buffered saline, pH 7.2. The formazan assay for anti-HIV activity was done on the purified retention fractions obtained by C-18 reverse-phase HPLC.
Anti-HIV- 1 data indicated that the major antiviral activity was confined to retention fraction (#22) following C-18 reverse-phase HPLC of tube fraction (# 16) obtained from gel-filtration HPLC. This retention fraction (#22) from C-18 reverse- phase HPLC that showed the major antiviral activity was then analyzed by mass spectrometry (MALDI-TOF and MALDl-CID) to determine the molecular weight, amino acid sequence and structure of the isolated insect anti-viral compound (compound of formula (I)). The insect anti-viral factor was analyzed by MALDI-CID and found to be a small molecular weight peptide (<1 kDa) having a non-peptide component. The compound is composed of 6 amino acids with a fatty acid at the N-terminal end of the molecule. The C-terminal end of the molecule contains an amino acid never before found in nature that gives the molecule a permanent positive charge at this end. The compound has broad- spectrum anti-viral activity against DNA and RNA viruses and cancer cells.
Additionally, the compounds of the invention can be prepared recombinantly, for example, the synthetic gene or cloned gene, or a variant thereof, coding for a compound of the instant invention can be expressed (e.g., over-expressed) in a cell, such as an insect cell or other eukaryotic or prokaryotic cell with appropriate machinery to produce such a compound. Isolation and preparation of expression cassettes and vectors can be readily prepared by an art worker with routine techniques available to the art worker in the biotechnology field. COMPOSITIONS
The compounds of the invention, including their salts, are administered to inhibit, prevent, achieve a reduction in at least one symptom associated with a cancerous and/or viral condition or other disease associated with inappropriate cellular growth and/or treat viral infections and/or cancer. Other agents can be included as described herein such as anti-cancer agents, chemotherapeutic agents, TNF, anti-viral agents and the like. Compositions comprising the compounds of the invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).
To achieve the desired effect(s), the compounds of the invention and/or combinations with other agents, may be administered as single or divided dosages. For example, the compounds of the invention can be administered in dosages of at least about 0.01 mg/kg to about 500 to 750 mg/kg, of at least about 0.01 mg/kg to about 300 to 500 mg/kg, at least about 0.1 mg/kg to about 100 to 300 mg/kg or at least about 1 mg/kg to about 50 to 100 mg/kg of body weight, although other dosages may provide beneficial results. The amount administered will vary depending on various factors including, but not limited to, the compound chosen, the disease, the weight, the physical condition, the health, the age of the subject, whether prevention or treatment is to be achieved, and if the compound is chemically modified. Such factors can be readily determined by the clinician employing animal models or other test systems that are available in the art. Administration of the therapeutic agents (compounds of the invention) in accordance with the present invention may be in a single dose, in multiple doses, in a continuous or intermittent manner, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of the compounds of the invention and/or other agents of the invention may be essentially continuous over a preselected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated.
To prepare the composition, compounds of the invention are synthesized, isolated or otherwise obtained, purified as necessary or desired and then lyophilized and stabilized as necessary or desired. The compounds of the invention can then be adjusted to the appropriate concentration, and optionally combined with other agents. The absolute weight of a given compound included in a unit dose can vary widely. For example, about 0.01 to about 2 g, or about 0.1 to about 500 mg, of at least one compound of the invention, or a plurality of compounds can be administered. Alternatively, the unit dosage can vary from about 0.01 g to about 50 g, from about 0.01 g to about 35 g, from about 0.1 g to about 25 g, from about 0.5 g to about 12 g, from about 0.5 g to about 8 g, from about 0.5 g to about 4 g, or from about 0.5 g to about 2 g. Daily doses of the compounds of the invention can vary as well. Such daily doses can range, for example, from about 0.1 g/day to about 50 g/day, from about 0.1 g/day to about 25 g/day, from about 0.1 g/day to about 12 g/day, from about 0.5 g/day to about 8 g/day, from about 0.5 g/day to about 4 g/day, and from about 0.5 g/day to about 2 g/day. Thus, one or more suitable unit dosage forms comprising the therapeutic compounds of the invention can be administered by a variety of routes including oral, parenteral (including subcutaneous, intravenous, intramuscular and intraperitoneal), rectal, dermal, transdermal, intrathoracic, intrapulmonary and intranasal (respiratory) routes. In some embodiments, the compounds of the invention are administered locally to tumor or cancer sites.
The therapeutic agents may also be formulated for sustained release (for example, using microencapsulation, see WO94/07529, and U.S. Patent No.4,962,091). The formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods available to the pharmaceutical arts. Such methods may include the step of mixing the therapeutic agents with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system.
When the therapeutic agents of the invention are prepared for oral administration, they are generally combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form. For oral administration, the therapeutic agents may be present as a powder, a granular formulation, a solution, a suspension, an emulsion or in a natural or synthetic polymer or resin for ingestion of the active ingredients from a chewing gum. The therapeutic agents may also be presented as a bolus, electuary or paste. Orally administered therapeutic agents of the invention can also be formulated for sustained release, e.g., the therapeutic agents can be coated, micro-encapsulated, or otherwise placed within a sustained delivery device. The total active ingredients in such formulations comprise from 0.001 to 99.9% by weight of the formulation. The phrase "pharmaceutically acceptable" means a carrier, diluent, excipient, and/or salt that is compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
Pharmaceutical formulations containing the therapeutic agents of the invention can be prepared by procedures available to the art using well-known and readily available ingredients. For example, the therapeutic agents can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, solutions, suspensions, powders, aerosols and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include water, buffers, as well as fillers and extenders such as starch, cellulose, sugars, mannitol, and silicic derivatives. Binding agents can also be included such as carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone. Moisturizing agents can be included such as glycerol, disintegrating agents such as calcium carbonate and sodium bicarbonate. Agents for retarding dissolution can also be included such as paraffin. Resorption accelerators such as quaternary ammonium compounds can also be included. Surface active agents such as cetyl alcohol and glycerol monostearate can be included. Adsorptive carriers such as kaolin and bentonite can be added. Lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols can also be included. Preservatives may also be added. The compositions of the invention can also contain thickening agents such as cellulose and/or cellulose derivatives. They may also contain gums such as xanthan, guar or carbo gum or gum arabic, or alternatively polyethylene glycols, bentones and montmorillonites, and the like.
For example, tablets or caplets containing the therapeutic agents of the invention can include buffering agents such as calcium carbonate, magnesium oxide and magnesium carbonate. Caplets and tablets can also include inactive ingredients such as cellulose, pregelatinized starch, silicon dioxide, hydroxy propyl methyl cellulose, magnesium stearate, microcrystalline cellulose, starch, talc, titanium dioxide, benzoic acid, citric acid, corn starch, mineral oil, polypropylene glycol, sodium phosphate, zinc stearate, and the like. Hard or soft gelatin capsules containing at least one therapeutic agent of the invention can contain inactive ingredients such as gelatin, microcrystalline cellulose, sodium lauryl sulfate, starch, talc, and titanium dioxide, and the like, as well as liquid vehicles such as polyethylene glycols (PEGs) and vegetable oil. Moreover, enteric-coated caplets or tablets containing one or more therapeutic agents of the invention are designed to resist disintegration in the stomach and dissolve in the more neutral to alkaline environment of the duodenum.
The therapeutic agents of the invention can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous, intraperitoneal or intravenous routes. The pharmaceutical formulations of the therapeutic agents of the invention can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension or salve.
Thus, the therapeutic agents may be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion containers or in multi-dose containers. As noted above, preservatives can be added to help maintain the shelve life of the dosage form. The compounds of the invention with optional other ingredients may form suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the compounds of the invention with optional other ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
These formulations can contain pharmaceutically acceptable carriers, vehicles and adjuvants that are well known in the art. It is possible, for example, to prepare solutions using one or more organic solvent(s) that is/are acceptable from the physiological standpoint, chosen, in addition to water, from solvents such as acetone, ethanol, isopropyl alcohol, glycol ethers such as the products sold under the name "Dowanol," polyglycols and polyethylene glycols, C] -C4 alkyl esters of short-chain acids, ethyl or isopropyl lactate, fatty acid triglycerides such as the products marketed under the name "Miglyol," isopropyl myristate, animal, mineral and vegetable oils and polysiloxanes. It is possible to add, if desired, additional ingredients chosen from antioxidants, surfactants, other preservatives, film-forming, keratolytic or comedolytic agents, perfumes, flavorings and colorings. Antioxidants such as t-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene and α-tocopherol and its derivatives can be added.
Additionally, the compounds of the invention are well suited to formulation as sustained release dosage forms and the like. The formulations can be so constituted that they release the therapeutic agents, for example, in a particular part of the intestinal or respiratory tract, possibly over a period of time. Coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide- glycolates, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, envelopes, and protective matrices are useful to coat indwelling devices, e.g., stents, catheters, peritoneal dialysis tubing, draining devices and the like.
For topical administration, the therapeutic agents may be formulated as is known in the art for direct application to a target area. Forms chiefly conditioned for topical application take the form, for example, of creams, milks, gels, dispersion or microemulsions, lotions thickened to a greater or lesser extent, impregnated pads, ointments or sticks, aerosol formulations (e.g., sprays or foams), soaps, detergents, lotions or cakes of soap. Other conventional forms for this purpose include wound dressings, coated bandages or other polymer coverings, ointments, creams, lotions, pastes, jellies, sprays, and aerosols. Thus, the therapeutic agents of the invention can be delivered via patches or bandages for dermal administration. Alternatively, the compounds of the invention can be formulated to be part of an adhesive polymer, such as polyacrylate or acrylate/vinyl acetate copolymer. For long-term applications it might be desirable to use microporous and/or breathable backing laminates, so hydration or maceration of the skin can be minimized. The backing layer can be any appropriate thickness that will provide the desired protective and support functions. A suitable thickness will generally be from about 10 to about 200 microns.
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The therapeutic agents can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122; 4,383,529; or 4,051 ,842. The percent by weight of a therapeutic agent of the invention present in a topical formulation will depend on various factors, but generally will be from 0.001 % to 95% of the total weight of the formulation, and typically 0.01 -85% by weight.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Drops, such as eye drops or nose drops, may be formulated with one or more of the therapeutic agents in an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs. Drops can be delivered via a simple eye dropper-capped bottle, or via a plastic bottle adapted to deliver liquid contents dropwise, via a specially shaped closure. The therapeutic agents may further be formulated for topical administration in the mouth or throat. For example, the active ingredients may be formulated as a lozenge further comprising a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the composition in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the composition of the present invention in a suitable liquid carrier.
The pharmaceutical formulations of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and salts of the type that are available in the art. Examples of such substances include normal saline solutions such as physiologically buffered saline solutions and water. Specific non-limiting examples of the carriers and/or diluents that are useful in the pharmaceutical formulations of the present invention include water and physiologically acceptable buffered saline solutions such as phosphate buffered saline solutions pH 7.0-8.0.
The therapeutic agents of the invention can also be administered to the respiratory tract. Thus, the present invention also provides aerosol pharmaceutical formulations and dosage forms for use in the methods of the invention. In general, such dosage forms comprise an amount of at least one of the agents of the invention effective to treat or prevent the clinical symptoms of a virus, cancer, tumor, indication or related disease. Any statistically significant attenuation of one or more symptoms of a virus and/or a cancer that has been treated pursuant to the method of the present invention is considered to be a treatment of such virus and/orcancer within the scope of the invention.
Alternatively, for administration by inhalation or insufflation, the composition may take the form of a dry powder, for example, a powder mix of the therapeutic agents and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges, or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator, insufflator, or a metered-dose inhaler (see, for example, the pressurized metered dose inhaler (MDI) and the dry powder inhaler disclosed in Newman, S. P. in Aerosols and the Lung, Clarke, S. W. and Davia, D. eds., pp. 197-224, Butterworths, London, England, 1984). Therapeutic agents of the present invention can also be administered in an aqueous solution when administered in an aerosol or inhaled form. Thus, other aerosol pharmaceutical formulations may comprise, for example, a physiologically acceptable buffered saline solution containing between about 0.1 mg/ml and about 100 mg/ml of one or more of the therapeutic agents of the present invention specific for the indication or disease to be treated. Dry aerosol in the form of finely divided solid compounds of the invention that are not dissolved or suspended in a liquid are also useful in the practice of the present invention. Compounds of the present invention may be formulated as dusting powders and comprise finely divided particles having an average particle size of between about 1 and 5 μm, alternatively between 2 and 3 μm. Finely divided particles may be prepared by pulverization and screen filtration using techniques well known in the art. The particles may be administered by inhaling a predetermined quantity of the finely divided material, which can be in the form of a powder. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual aerosol dose of each dosage form need not in itself constitute an effective amount for treating the particular infection, indication or disease since the necessary effective amount can be reached by administration of a plurality of dosage units. Moreover, the effective amount may be achieved using less than the dose in the dosage form, either individually, or in a series of administrations.
For administration to the upper (nasal) or lower respiratory tract by inhalation, the therapeutic agents of the invention are conveniently delivered from a nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Nebulizers include, but are not limited to, those described in U.S. Patent Nos. 4,624,251 ; 3,703,173; 3,561 ,444; and 4,635,627. Aerosol delivery systems of the type disclosed herein are available from numerous commercial sources including Fisons Corporation (Bedford, Mass.), Schering Corp. (Kenilworth, NJ) and American Pharmoseal Co., (Valencia, CA). For intra-nasal administration, the therapeutic agent may also be administered via nose drops, a liquid spray, such as via a plastic bottle atomizer or metered-dose inhaler. Typical of atomizers are the Mistometer (Wintrop) and the Medihaler (Riker).
Furthermore, the active ingredients may also be used in combination with other therapeutic agents, for example, pain relievers, anti-inflammatory agents, antihistamines, antimicrobial agents, bronchodilators and the like, whether for the conditions described or some other condition.
The compositions are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub- dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient.
The present invention further pertains to a packaged pharmaceutical composition for the prevention, inhibition or treatment of a viral infection and/or cancer such as a kit or other container. The kit or container holds a therapeutically effective amount of a pharmaceutical composition for the prevention, inhibition or treatment of a viral infection and/or cancer, and instructions for using the pharmaceutical composition for the prevention, inhibition or treatment of a viral infection and/or cancer. The pharmaceutical composition includes at least one compound of the present invention, in a therapeutically effective amount such that a viral infection and/or cancer is prevented, inhibited or treated. The composition can also contain other anti-cancer agents and/or anti-viral agents as discussed above.
If desired, the activity of virus and/or cancer after application of the composition can be observed by any method including direct and indirect methods of detecting virus and/or cancer activity. Quantitative, qualitative, and semiquantitative methods of determining viral and/or cancer activity are all contemplated. Organisms that contain viruses and/or cancer include mammals such as humans.
The compounds of this invention are useful in the treatment or prophylaxis of viral infections and/or cancer in animals or in man. COMBINATION THERAPIES
It is also possible to combine any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
The combination therapy may provide "synergy" and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Anti-Virals The invention contemplates compounds, compositions and methods that employ combinations of the compounds of the invention with other available anti-viral therapeutics. According to the invention, a combination of compounds of the invention with available anti-viral agents can improve the spectrum of viruses against which those anti-virus agents are effective. Thus, the invention contemplates combinations of the present compounds of the invention with one or more additional anti-viral agents. Any anti-viral agent available can be used with the present compounds of the invention. Further, in some cases, surgical treatment is performed in addition to these methods (combination or single therapy) to improve the effect of the treatment.
Examples of anti-viral agents that may be used in conjunction with the compounds of the invention include vaccines, amantadine, rimantadine, pleconaril, aciclovir, zidovudine (AZT), lamivudine, fomivirsen, zanamivir (Relenza), oseltamivir (Tamiflu), interferons, antibodies, e.g., monoclonal antibodies (e.g., a monoclonal drug to help fight respiratory syncytial virus), Abacavir, Aciclovir, Acyclovir, Adefovir, Amantadine, Amprenavir, Arbidol, Atazanavir, Atripla, Brivudine ,Cidofovir, Combivir, Darunavir, Delavirdine, Didanosine, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Entry inhibitors, Famciclovir, Fixed dose combination (antiretroviral), Fomivirsen, Fosamprenavir, Foscamet, Fosfonet, Fusion inhibitor, Ganciclovir, Gardasil, Ibacitabine, Imunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Integrase inhibitor, Interferon type III, Interferon type II, Interferon type I, Interferon, Lamivudine, Lopinavir, Loviride, MK-0518, Maraviroc, Moroxydine, Nelfinavir, Nevirapine, Nexavir, Nucleoside analogues, Oseltamivir, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Protease inhibitor, Reverse transcriptase inhibitor, Ribavirin, Rimantadine, Ritonavir, Saquinavir, Stavudine, Synergistic enhancer (antiretroviral), Tenofovir, Tenofovir disoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir, Zidovudine or a combination thereof.
Anti-Cancer
The invention also contemplates compounds, compositions and methods that employ combinations of the compounds of the invention with other available anti-cancer therapeutics. Dosages of conventional anti-cancer agents are often kept as low as possible because side effects may be observed at higher dosages. According to the invention, a combination of compounds of the invention with available anti-cancer agents can improve the spectrum of cancers against which those anti-cancer agents are effective and reduce the required dosage of those anti-cancer agents. Thus, the invention contemplates combinations of the present compounds of the invention wiuTone or more anti-cancer or carcinostatic agents. Any anti-cancer an/or carcinostatic agent available can be used with the present compounds of the invention. Further, in some cases, radiotherapy or surgical treatment is performed in addition to these methods (combination or single therapy) to improve the effect of the treatment.
Examples of anti-cancer7chemotherapeutic agents that may be used in conjunction with the compounds of the invention include Altretamine, Bleomycin, Busulphan, Calcium Folinate, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Liposomal doxorubicin, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Pentostatin, Procarbazine, Raltitrexed, Streptozocin, Tegafur- uracil, Temozolomide, Thiotepa, Tioguanine/Thioguanine, Topotecan, Treosulfan, Vinblastine, Vincristine, Vindesine, Vinorelbine or a combination thereof. The invention will be further described by reference to the following detailed examples, which are given for illustration of the invention, and are not intended to be limiting thereof.
EXAMPLE 1: Anti-Viral Activity The synthesized structure Myristoyl-Cys-Ala-Val-Ala-Tyr-(3 methyl)His-OMe was used to obtain the anti-EBV results and cytotoxicity assay data that follow.
Testing of the synthesized compound was done at the National Institute of Allergy and Infectious Diseases (NIAID) - Antimicrobial Acquisition and Coordinating Facility
(Birmingham, AL) for anti-viral activity. A DNA hybridization aassay for anti-EBV activity using the Akata cell (B-lymphocyte) and two cytotoxicity assays using Human
Foreskin Fibroblast (HFF) cells were done. The methods of testing of the synthetic compound are as follows.
Assay Systems for Determining Antiviral Activity Against EBV and
Toxicity to Lymphoblastic Cells: Epstein-Barr Virus (EBV).
Screening Assay for EBV Activity. The initial system to be used to determine antiviral activity against EBV was virus capsid antigen (VCA) production in Daudi cells
(a lymphoblastoid B cell line) using an Enzyme Linked Immunosorbent Assay (ELISA).
Six concentrations of drug covering a range of 50 mg/ml to 0.03 mg/ml was utilized. Using the results obtained from untreated and drug treated cells, an EC50 (e.g., Effective
Concentration; the dosage at which the desired response is present for 50 percent of the population) can be calculated. Selected compounds that have good activity against EBV
VCA production without toxicity were tested for their ability to inhibit EBV DNA synthesis. Cytotoxicity. In each assay system utilized, drug treatment of uninfected cells was incorporated to obtain as much toxicity data as possible. For calculation of the SI, it is very important that the data on toxicity be at least as reliable as the results for efficacy.
As part of the EBV primary screening and confirmation studies preliminary evidence of toxicity was obtained as part of the assay system using a colormetric method using MTS. Confirmation of Drug Activity against EBV DNA Production using in situ
DNA Hybridization Assay. All compounds that had an selective index (SI) >10 in the screening assay or ones selected were confirmed in a hybridization assay that measures the amount of EBV DNA produced by P3HR-1 (Epstein-Barr virus strain P3HR-1) infected cells. A wide range of drug (compound of interest) concentration was utilized so an accurate EC50 was calculated. Uninfected control cells treated with drug were utilized as another measure of drug toxicity. It is entirely possible however, that results obtained using assays for VCA production and DNA synthesis may not always correlate since the two events may be independent. Screening and Confirmation Assays for Toxicity:
Neutral Red Uptake Assay in Human Foreskin Fibroblast (HFF) Cells. Twenty-four hr prior to assay, Human Foreskin Fibroblasts (HFF) cells were plated into 96 well plates at a concentration of 2.5 x 104 cells per well. After 24 hr, the media was aspirated and 125 μl of each drug (compound of interest; e.g., a compound of formula XX) concentration was added to the first row of wells and then diluted serially 1 :5 using the automated Bio-Mek Liquid Handling System. The plates were then incubated in a CO2 incubator at 37°C for seven days. At this time the media/drug was aspirated and 200 μl/well of 0.01% neutral red in DPBS was added. This was incubated in a CO2 incubator for 1 hr. The drug was aspirated and the cells were washed using a Nunc Plate Washer. After removing the DPBS wash, 200 μl/well of 50% ETOH/1% glacial acetic acid (in H2O) was added. The plates were rotated for 15 min and the optical densities were read at 550 nm on a plate reader. EC50 values were calculated using a computer program.
(The concentration at which 50% of the cell damage was prevented (EC50) or the dosage at which the desired response is present for 50 percent of the population; and the concentration at which 50% of cytotoxicity was prevented (CC50). CC50 %/EC5o % (SI, selective index) can be used as the index of effectiveness.) Cell Proliferation Assay in Human Foreskin Fibroblast (HFF) Cells. Twenty- four hr prior to assay, HFF cells were seeded in 6-well plates at a concentration of 2.5 x 104 cells per well in MEM containing 10% FBS. On the day of the assay, drugs (compound of interest; e.g., a compound of formula XX) were diluted serially in MEM containing 10% FBS at increments of 1 :5 covering a range from 100 μg/ml to 0.03 μg/ml. For drugs that have to be solubilized in DMSO, control wells received MEM containing 1.0% DMSO. The media from the wells was then aspirated and 2 ml of each drug concentration was then added to each well. The cells were then incubated in a CO2 incubator at 37°C for 72 hr. At the end of this time, the media-drug solution was removed and the cells washed. One ml of 0.25% trypsin was added to each well and incubated until the cells started to come off of the plate. The cell-media mixture was then
5 pipetted up and down vigorously to break up the cell suspension and 0.2 ml of the mixture was added to 9.8 ml of Isoton 111 and counted using a Coulter Counter. Each sample was counted 3 times with 2 replicate wells per sample.
The in vitro testing results for the synthesized compound are depicted in Table 1 below.
Table I
EBV Assay
Figure imgf000088_0001
EC = Effective Concentration CC = Cytotoxic Concentration Herpes Toxicity Cell Proliferation Assay
Figure imgf000088_0002
IC=Inhibitory Concentration HFF=Human Foreskin Fibroblast
Herpes Toxicity Neutral Red Uptake Assay
Figure imgf000089_0001
As can be seen from Table I5 the synthesized structure of Formula (I) has excellent anti-viral activity against the Epstein-Barr Virus (EBV )- Effective 5 Concentration 90% (EC90) at 20 μM or inhibited viral replication by 90%. The DNA Hybridization assay was done to determine anti-EBV activity using the Akata cell line (B-lymphocyte from Burkitt's Lymphoma patient) (N. Shimizu, A. Tanabe-Tochikura, Y. Kuroiwa and K. Takada, Isolation of Epstein-Barr Virus (EBV)-Negative cell clones from the EBV-Positive Burkitt's Lymphoma (BL) line Akata: Malignant phenotypes of
10 BL cells are dependent on EBV, J. Virol. 68, 6069-6073; N. Shimizu, H. Yoshiyama and K. Takada, Clonal propagation of Epstein-Barr virus (EBV) recombinants in EBV- negative Akata cells, J. Virol. 70, 7260-7263, 1996; J. Komano and K. Takada, Role of bci-2 in Epstein-Barr virus-induced malignant conversion of Burkitt's Lymphoma cell line Akata, J. Virol. 75, 1561 -1564, 2001 ). Cytotoxicity studies were done using human
15 foreskin fibroblast (HFF) cells.
ANTI-EPSTEIN-BARR VIRUS DATA - RESULTS
An Effective Concentration (EC) of >20 μM of the synthetic antiviral compound inhibited viral replication in Akata cells (B-lymphocyte/Burkitt's Lymphoma) by 50% (EC50) compared with an EC50 of 17 μM for the Acyclovir control. Antiviral compound 0 was nearly equivalent then to Acyclovir control in antiviral activity.
An Effective Concentration (EC) of >20 μM of the synthetic antiviral compound also inhibited viral replication in Akata cells by 90% (EC90). So the same antiviral compound concentration (>20 μM) also inhibited viral replcation by 90%. An Acyclovir control (EC90) was not done. This indicates that the antiviral compound effectively 5 stopped all viral replication (EC90) at >20 μM. The antiviral compound disclosed herein was therefore as effective in preventing viral replication of EBV as Acyclovir. Acyclovir is an antiviral drug commonly used for treatment of herpes simplex virus infection.
The Cytotoxic Concentration (CC50) in the cytotoxicity assay test was 74 μM. This means that a concentration of 74 μM inhibited cell divison by 50%. The CC50 was nearly 4-times greater than the EC50 of the synthetic antiviral compound. So viral replication would be inhibited at >20 μM (EC50 and ECg0) before the antiviral compound would become toxic to cells at 74 μM. Antiviral activity would thus still be effective before the antiviral compound became toxic to cells. A Herpes-Toxicity-Cell Proliferation Assay was done in Human Foreskin
Fibroblast (HFF) cells with the synthetic antiviral compound. An IC50 of > 100 μM was needed to inhibit cell proliferation of 50%. This compares with 40 μM for the Ganciclovir control. Thus the antiviral compound is at least 2.5-times less toxic than Ganciclovir. The antiviral compound was equal to Acyclovir which also had an IC50 of >100 μM. The EC50 and EC90 for the antiviral compound were both >20 μM. When compared with an IC50 of > 100 μM for this toxicity assay, then this would give a Selectivity Index (SI) of 5 for antiviral activity. The fibroblast or connective tissue cell is the most common animal tissue cell and is used as a general tissue culture cell to test for drug cytotoxic activity. A Herpes-Toxicity-Neutral Red Assay was done in Human Foreskin Fibroblast
(HFF) cells with the synthetic antiviral compound. A CC50 of >300 μM was obtained for the antiviral compound when compared with Ganciclovir and Acyclovir which both had a CCsoof > 100 μM. Thus the antiviral compound was 3-times less toxic than these two antiviral drugs which are currently in clinical use. The EC50 and EC90 for the antiviral compound were both >20 μM. When compared with a CC50 of >300 μM for this cytotoxicity assay, this would give a Selectivity Index (SI) of 15, a very significant SI number for antiviral activity. This also means that higher dosages of the antiviral compound, when compared with Ganciclovir and Acyclovir, could be given before the antiviral compound became too toxic to host cells. The Cell Proliferation Toxicity Assay determines the effect of drug treatment on dividing cells and the drug concentration that inhibits cell growth by 50% (IC5o). The Neutral Red Toxicity Assay determines direct cell cytotoxicity (CC50). This toxicity assay quantitates the number of viable cells present after drug treatment. The Selectivity Index (SI) average of the antiviral compound for both the Cell Proliferation Toxicity Assay (SI=5) and the Neutral Red Toxicity Assay (SI=I 5) gives an SI average of 10. EBV is a double-stranded DNA, enveloped virus (Herpesviridae family). The antiviral compound most likely inhibits viral DNA synthesis. The anti-EBV data and Cytotoxicity results for the antiviral and anticancer compound were obtained at the National Institute of Allergy and Infectious Diseases (NIAID)-Antimicrobial Acquisition and Coordinating Facility, Birmingham, AL.
Furthermore, the synthesized compound of formula (I) showed very low cytotoxicity to host cells. NIAID testing found that its cytotoxicity was only one-third that of Acyclovir and Ganciclovir, which were two antivirals used as cellular controls. The vast majority of new potential antiviral and antibiotic agents are eliminated because they are too cytotoxic to host cells. Being able to inactivate a virus inside a host cell without killing the host cell is very difficult for an antiviral drug to do. This attribute makes this a very strong and clinically relevant antiviral drug. EXAMPLE 2: Anti-Cancer Activity In addition to the results from the testing done at NIAID which indicate that a synthesized compound of formula (I) is very effective against the Epstein-Barr virus, the synthesized compound is also an anti-cancer drug. The National Cancer Institute of NIH has tested the compound for anti-cancer activity using established procedures (M. C. Alley, D. A. Scudiero, A. Monks, M. L. Hursey, M. J. Czerwinski, D. L. Fine, B. J. Abbott, J. G. Mayo, R. H. Shoemaker and M. R. Boyd, Feasibility of Drug Screening with Panels of Human Tumor Cell Lines using a Microculture Tetrazolium Assay, Cancer Research 48, 589-601 , 1988; M. R. Grever, S. A. Schepartz and B. A. Chabner, The National Cancer Institute: Cancer Drug Discovery and Development Program, Seminars in Oncology 19, 622-638, 1992; M. R. Boyd and K. D. Paull, Some Practical Considerations and Applications of the National Cancer Institute In Vitro Anticancer Drug Discovery Screen, Drug Development Research 34, 91 -109, 1995). ANTI-CANCER DATA - RESULTS
The synthesized compound was screened here for anti-cancer activity against 56 different live tumor cell lines in tissue culture by the National Cancer Institute of NlH (see Figure 1). NCl found that 34 out of the 56 tumor cell lines were very sensitive (growth inhibition or killing of cancer cells) to the compound. The tumor cell lines sensitive to the compound included: Non-Small Cell Lung Cancer, Colon Cancer, Breast Cancer, Ovarian Cancer, Leukemia, Renal Cancer, Melanoma, CNS (Brain) Cancer. For example, a compound of synthesized formula (I) or Myristoyl-Cys-Ala-Val-Ala-Tyr-(3 methyl)His-OMe at 10 μM was effective (Growth Inhibition of tumor cells greater than 50%) against 4 out of 7 renal cancers, 5 out of 8 melanoma cancers, 3 out 6 brain cancers, 2 out of 5 ovarian cancers, 5 out of 5 leukemias, 7 out of 9 non-small cell lung caners, 5 out of 7 colon cancers, and 3 out of 7 breast cancers. The compound has essentially no cytotoxic activity to human fibroblast cells (connective tissue cells), the most common animal body cell. Thus, it does not act as a poison to human non-cancer cells. The National Cancer Institute finds that their in vitro screen is an effective selector of compounds with in vivo antitumor activity. See Figure 1 for bar graph of anti-cancer data by NCl of synthesized compound. EXAMPLE 3: Anti-Fungal Activity
Antifungal in vitro susceptibility activity (10 μg/10 μl), using the synthesized (3 methyl) version of the compound against three genera (two mold, one yeast) was found using Sabouraud dextrose agar, a selective medium for fungal and yeast growth. Compounds of the invention included the synthesized (3 methyl) compound contains an imidazole ring at their C-terminal end (see, for example, a compound of forumula (I)). The N-terminal end is lipophilic which likely helps the synthesized (3 methyl) compound in crossing the fungal cell wall. Many anti-fungal drugs contain an imidazole ring.
Imidazole and triazole inhibit an enzyme (cytochrome P450) needed for biosynthesis of ergosterol, an important sterol found in fungal cell membranes. New antifungal drugs are needed as many fungal infections have acquired multidrug resistance. Antifungal drugs containing the azole ring have also been found to be effective against the tuberculosis (TB) bacterium that currently infects one-third of the world's population (Seward, H. E., J. Biol. Chem., 281 , 39437-39443, 2006; Munro, A. W., Science Daily, March 12, 2007). Multidrug resistant strains of TB have emerged and thus new anti-TB drugs are needed. All patents and publications referenced or mentioned herein are indicative of the levels of skill of those skilled in the art to which the invention pertains, and each such referenced patent or publication is hereby incorporated by reference to the same extent as if it had been incorporated by reference in its entirety individually or set forth herein in its entirety. Applicants reserve the right to physically incorporate into this specification any and all materials and information from any such cited patents or publications.
The specific methods and compositions described herein are representative of preferred embodiments and are exemplary and not intended as limitations on the scope of the invention. Other objects, aspects, and embodiments will occur to those skilled in the art upon consideration of this specification, and are encompassed within the spirit of the invention as defined by the scope of the claims. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, or limitation or limitations, which is not specifically disclosed herein as essential. The methods and processes illustratively described herein suitably may be practiced in differing orders of steps, and tjjat they are not necessarily restricted to the orders of steps indicated herein or in the claims. As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "an antibody" includes a plurality (for example, a solution of antibodies or a series of antibody preparations) of such antibodies, and so forth. Under no circumstances may the patent be interpreted to be limited to the specific examples or embodiments or methods specifically disclosed herein. Under no circumstances may the patent be interpreted to be limited by any statement made by any Examiner or any other official or employee of the Patent and Trademark Office unless such statement is specifically and without qualification or reservation expressly adopted in a responsive writing by Applicants. The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intent in the use of such terms and expressions to exclude any equivalent of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, it will be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

Claims

WHAT IS CLAIMED IS:
1. One embodiment provides a compound of formula (XX):
Figure imgf000095_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent; X6 is at least one amino acid or absent; R is independently at each occurrence H or (C|-C6)alkyl; R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y1 independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxy!, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group;
R4 and R3 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-CiO)alkyl, (C2-C, 0)alkenyl, (C2-C10)alkynyl, (C,-C10)haloalkyl, (C3-C,0)cycloalkyl, (C3-
Cιo)cycloalkyl(Ci-C|0)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (C|-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Cι-Cio)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Cr Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C]-C6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C|-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (C|-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, provided that when X1 is C6-C25alkylcarbonyl, X3 is not Ala, X4 is not VaI and X5 is not Ala.
2. The compound of claim 1 , wherein the steroid is cholesterol, vitamin A, or vitamin D.
3. The compound of claim 1 , wherein X3-X5 are independently any non-polar amino acid and X6 is absent.
4. The compound of claim 1 , wherein X6 is any non-polar amino acid.
5. The compound of claim 1 , wherein X3 is alanine, X4 is valine, X5 is alanine, and X6 is absent.
6. The compound of claim 1 , wherein the compound forms a dimer.
7. The compound of claim 1 , wherein the X1 is myristoyl or palmitoyl.
8. The compound of claim 1 , wherein X2 is cysteine.
9. The compound of claim 1 , wherein R1 and R2 are methyl.
10. The compound of claim 1 , wherein R3 is OMe.
1 1. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
12. A unit dosage form comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
13. A method to inhibit replication of a virus in a cell comprising contacting said cell with a compound of claim 1 in an amount effective to inhibit the replication of the virus in said cell.
14. The method of claim 13, wherein the virus is human immunodeficiency virus (HIV), herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or Epstein Barr Virus (EBV).
15. A method to inhibit replication of a virus in a cell comprising contacting said cell with a compound of formula (XX):
Figure imgf000098_0001
wherein
X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (Ci-C6)alkyl; R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (C|-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group; R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (CrCi0)alkyl,
(C2-C io)alkenyl, (C2-C, 0)alkynyl, (C,-C,0)haloalkyl, (C3-Ci0)cycloalkyl, (C3- Cio)cycloalkyl(C|-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (C|-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Cιo)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (C|- Ci0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two R together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof; Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the replication of the virus in said cell, provided the virus is not HIV or herpes simplex virus-1 (HSV-I).
16. The method of claim 15, wherein the virus is not herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis viruses.
17. The method of claim 15 wherein the virus is an Epstein Barr Virus (EBV).
18. A method to inhibit a viral infection in vitro or in vivo comprising contacting a sample in need of such treatment with a compound of claim 1 with an amount effective to inhibit viral infection.
19. The method of claim 18, wherein the virus is human immunodeficiency virus (HIV), herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or Epstein Barr Virus (EBV).
20. A method to inhibit a viral infection in vitro or in vivo comprising contacting a sample in need of such treatment with a compound of formula (XX):
Figure imgf000101_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-Xs are any amino acid or absent; X6 is at least one amino acid or absent;
R is independently at each occurrence H or (Ci-C6)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (C)-C6)aikyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C,o)alkenyl, (C2-C ,0)alkynyl, (Ci-Cio)haloalkyl, (C3-Ci0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Ci0)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (C|-CiO)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- Cιo)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C|-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (CrC6)alkyl, (Ci-C6)haloalkyl, (C3-
C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (C|-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit viral infection, provided the virus is not HlV or herpes simplex virus- 1 (HSV-I).
21. The method of claim 20, wherein the viral infection is not a herpes simplex virus- 2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection.
22. The method of claim 20 wherein the virus is an Epstein Barr Virus (EBV).
23. The method of claim 18 or 20, wherein the contacting in vivo.
24. A method to treat a viral infection comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
25. The method of claim 24, wherein the virus is human immunodeficiency virus (HlV), herpes simplex virus- 1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or Epstein Barr Virus (EBV).
26. A method to treat a viral infection comprising administering to a subject in need thereof an effective amount of a compound of formula (XX):
Figure imgf000104_0001
wherein
X is Q-C^alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (Ci-C6)alkyl; R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any ary heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C ,o)alkenyl, (C2-Cl0)alkynyl; (C,-Cιo)haloalkyl, (C3-C,o)cycloalkyl, (C3-
Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (CrC6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Cιo)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C1-C^aCyI, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Q- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1-4 (C|-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, provided the virus is not HIV or herpes simplex virus-1 (HSV-I).
27. The method of claim 26, wherein the viral infection is not a herpes simplex virus- 2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection.
28. The method of claim 26, wherein the virus is an Epstein Barr Virus (EBV).
29. The method of claim 24 or 26, wherein the subject is a mammal.
30. The method of claim 29, wherein the mammal is a human.
31. The method of claim 24 or 26, wherein the compound is formulated with a pharmaceutically acceptable carrier.
32. The method of claim 24 or 26, wherein a second active ingredient is administered.
33. A method to inhibit tumor growth in vitro or in vivo comprising contacting a cell in need of such treatment with a compound of formula (XX):
Figure imgf000107_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (Ci-Cό)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (C|-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Cι-Cio)alkyl, (C2-C,o)alkenyl, (C2-Cl0)alkynyl, (Cj-COhaloalkyl, (C3-C,0)cycloalkyl, (C3-
C|0)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, cyano, nitro, (C)-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cιo)alkyl, (C|- Cιo)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C|-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C]-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-Cό)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (d-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, so as to inhibit tumor growth.
34. The method of claim 33wherein the contacting is in vivo.
35. The method of claim 33 wherein the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal.
36. A method to treat symptoms of cancer in a subject comprising administering to a " subject in need thereof an effective amount of a compound of formula (XX):
Figure imgf000110_0001
wherein
X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent; X6 is at least one amino acid or absent; R is independently at each occurrence H or (C|-C6)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group; R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C io)alkenyl, (C2-C,0)alkynyl, (Ci-Cio)haloalkyl, (C3-C)0)cycloalkyl, (C3- Cio)cycloalkyl(C|-Cιo)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 5 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (C]-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence I O comprises H, (Ci-Cιo)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (C)- Ci0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (Cr 15 C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, 0 nitro, (Ci-C6)haloalkyl, (Cι-Cό)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C|-C6)alkyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl 5 group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (C|-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- 0 C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof.
37. A method to inhibit neoplastic in a subject comprising administering to a subject in need thereof an effective amount of a compound of formula (XX):
Figure imgf000112_0001
wherein
X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (Ci-C6)alkyl;
i n R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C io)alkenyl, (C2-C10)alkynyl, (d-C10)haloalkyl, (C3-C ,0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cιo)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Cr Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (d- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-Cό)haloalkoxy, or carboxyamido, or any combination thereof; Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is O5 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (C)-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-Cό)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R comprises cyano, CO2R, or a group of formula -C(=X )N(R )2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (CrC6)haloaIkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof.
38. The method of claim 37, wherein the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T- cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma.
39. The method of claim 38, wherein the non-Hodgkin's lymphoma is Burkitt's lymphoma.
40. The method of claim 36 or 37, wherein the subject is a mammal.
41. The method of claim 40, wherein the mammal is a human.
42. The method of claim 36 or 37, wherein the compound is formulated with a pharmaceutically acceptable carrier.
43. The method of claim 42, wherein a second active ingredient is administered.
44. A compound of formula (XX):
Figure imgf000115_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (Ci-C6)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY1, NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C ιo)alkenyl, (C2-C, 0)alkynyl, (C1-C, 0)haloalkyl, (C3-C,0)cycloalkyl, (C3- Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, cyano/nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (C,-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (C-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cιo)alkyl, (C,- C,o)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C,-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (Q-Ce^aloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (CrC6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1-4 (C,-C6)alkyl, halo, OR, NRB 2, (C|-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- Cg)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, provided that when X1 is C6- C25alkylcarbonyl, X3 is not Ala, X4 is not VaI and X5 is not Ala for use in medical therapy.
45. The use of claim 44, wherein the medical therapy is treatment of cancer.
46. The use of claim 44, wherein the medical therapy is treatment or prevention of a viral infection.
47. The use of a compound of formula (XX):
Figure imgf000118_0001
wherein
X1 is C6-C25alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine); X3-X5 are any amino acid or absent; X6 is at least one amino acid or absent; R is independently at each occurrence H or (C|-C6)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group; R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-Ci0)alkenyl, (C2-C iO)alkynyl, (Ci-C|0)haloalkyl, (C3-C,o)cycloalkyl, (C3- Ci0)cycloalkyl(Ci-Ci0)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (CrC6)alkyl, OR, halo, NR2, cyano, nitro, (C,-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Cι-Cio)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (CrC6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1-4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- Cg)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ct-C6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (CrC6)alkyl, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating or inhibiting viral infection, provided the viral infection is not a HIV or herpes simplex virus- 1 (HSV-I ) infection.
48. The use of claim 47, wherein the viral infection is not a herpes simplex virus-2 (HSV-2), vesicular stomatitis virus (VSV), parainfluenza-3, coxsackie B3, or sindbis virus infection.
49. The use of claim 47, wherein the viral infection is an Epstein Barr Virus (EBV) infection.
50. The use of a compound of formula (XX):
Figure imgf000120_0001
I 19 wherein
X1 is Cό-C^alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (Ci-C6)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY1, NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C 10)alkenyl, (C2-C|0)alkynyl, (Ci-Cio)haloalkyl, (C3-C 10)cycloalkyl, (C3-
Cio)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (C|-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, 0RA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cιo)alkyl, (Cι-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cιo)alkyl, (Ci- Ci0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1 -4 (CrC6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (C1- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (CrC6)haloalkyl, (C3-
C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (Ci-C6)haloalkyl, (C|-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein . each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (C|-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (C|-C6)alkyl, OR, halo, NR2, nitro, (CrC6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof, provided that when X1 is C6-
C25alkylcarbonyl, X3 is not Ala, X4 is not VaI and X5 is not Ala to prepare a medicament for treating or inhibiting viral infection.
51. The use of claim 50, wherein the viral infection is a HIV, herpes simplex virus-1 , herpes simplex virus-2, vesicular stomatitis virus, parainfluenza-3, coxsackie B3, sindbis virus, or EBV infection.
52. The use of a compound of formula (XX):
Figure imgf000123_0001
wherein
X1 is Cό-C^alkylcarbonyl, a transporter peptide sequence, HIV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (C]-C6)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Ci-C6)alkyl which can be optionally substituted by hydroxy!, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring; R3 is any carboxy protecting group;
R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C,0)alkenyl, (C2-C ,0)alkynyl, (Ci-Cio)haloalkyl, (C3-C,0)cycloalkyl, (C3- Cιo)cycloalkyl(Ci-Cio)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (Ci-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci-Ci0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (Ci- Cιo)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (C|-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (CrC6)alkyI, OR, halo, NR2, nitro, (C,-C6)haloalkyl, (Ci-
C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (d-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (C)-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(0)p wherein p is O, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C,-C6)alkyl, (C,-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (C|-C6)alkyl, halo, OR, NRB 2, (C|-C6)haloalkyl, (Ci-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-
C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (d-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1-4 (C|-C6)alkyl, OR, halo, NR2, nitro, (C|-C6)haloalkyl, (C,-C6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof to prepare a medicament for inhibiting tumor growth, inhibiting neoplastic disease or treating cancer in a subject.
53. The use of claim 52, wherein the tumor is located in the breast, lung, thyroid, lymph node, blood, genitourinary system, kidney, ureter, bladder, ovary, testis, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissues, skin, cervix, anus, retina, and/or heart of a mammal.
54. The use of claim 52, wherein the neoplasm is from acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy-cell leukemia or non-Hodgkin's lymphoma.
55. The use of claim 54, wherein the non-Hodgkin's lymphoma is Burkitt's lymphoma.
56. The use of a compound of formula (XX):
Figure imgf000126_0001
wherein
X is C6-C25alkylcarbonyl, a transporter peptide sequence, HlV-TAT peptide sequence, Drosophila Antennapedia peptide sequence, or a steroid; X2 is any amino acid or absent or X1 and X2 taken together are Dipalmitoyl-S-glyceryl-cysteine (Pam 2- cysteine) or Tripalmitoyl-S-glyceryl-cysteine (Pam 3-cysteine);
X3-X5 are any amino acid or absent;
X6 is at least one amino acid or absent;
R is independently at each occurrence H or (C|-C6)alkyl;
R1 and R2 independently comprise H, aryl, heteroaryl or alkyl, wherein any aryl, heteroaryl, or alkyl is optionally mono- or pluri-substituted with halo, hydroxy, CO2Y, CONYY', NYY', oxo, alkoxy, aryl, cycloalkyl, or heterocyclyl; wherein any aryl, heteroaryl, cycloalkyl, heterocyclyl, or alkyl carbon atom can be replaced with a heteroatom selected from the group consisting of O, N, S, S(O), and S(O)2, wherein Y and Y' independently at each occurrence comprises H, or (Cj-C6)alkyl which can be optionally substituted by hydroxyl, amino, COOY, heterocylyl, aryl, or heteroaryl; or, Y and Y' can together with a nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring;
R3 is any carboxy protecting group; R4 and R5 are each independently H, halo, cyano, nitro, C(O)R6, (Ci-Cio)alkyl, (C2-C, o)alkenyl, (C2-C,0)alkynyl, (Ci-C,o)haloalkyl, (C3-C10)cycloalkyl, (C3- Cio)cycloalkyl(Ci-C|0)alkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally independently substituted with 1 -4 (C,-C6)alkyl, OR, halo, NR2, cyano, nitro, (Ci-C6)haloalkyl, (C,-C6)haloalkoxy, carboxamido, heterocyclyl, aryl, or heteroaryl, or any combination thereof, wherein the aryl and heteroaryl groups are optionally independently substituted with 1 -4 (Ci-C6)alkyl, OR, halo, NR2, or carboxyamido; wherein R6 is (C,-C6)alkyl, ORA, or N(RB)2, RA independently at each occurrence comprises H, (Cι-Cio)alkyl, (Ci-Cio)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RB independently at each occurrence comprises H, (Ci-Cio)alkyl, (C|- C]0)haloalkyl, (C3-C7)cycloalkyl, heterocyclyl, (Ci-C6)acyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with 1-4 (C,-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci- C6)haloalkoxy, or carboxyamido, or any combination thereof, or two RB together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring optionally comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O), and S(O)2, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclic ring of RB is optionally substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or any combination thereof;
Q1, Q2, Q3 and Q4 are each independently CR7, N, O, or S(O)P wherein p is 0, 1 , or 2; each R7 is independently H, halo, N(RB)2, (C|-C6)alkyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heteroaryl, or R8, wherein any alkyl, cycloalkyl, aryl, or heteroaryl group of R7 is optionally independently substituted with 1 -4 (Ci-C6)alkyl, halo, OR, NRB 2, (C)-C6)haloalkyl, (C|-C6)haloalkoxy, carboxamido, or R8, or any combination thereof, wherein each R8 comprises cyano, CO2R, or a group of formula -C(=X8)N(R9)2, each R9 is independently H, R, OR, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C8)cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally independently substituted with 1-4 (Ci-C6)alkyl, OR, halo, NR2, nitro, (C]-C6)haloalkyl, (Ci-C6)haloalkoxy, or carboxyamido, or two R9 together with a nitrogen atom to which they are bonded form a heterocyclyl optionally comprising one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O)2, and NRB, optionally independently substituted with 1 -4 (CrC6)alkyl, OR, halo, NR2, nitro, (Ci-C6)haloalkyl, (CrC6)haloalkoxy, or carboxyamido, and X8 is O, S, NR, NOR, NNHR, or NNH-aryl; or a pharmaceutically acceptable salt thereof to prepare a medicament to treat a fungal, bacterial, protozoal, or helminthic infection.
57. The use of claim 56, wherein the medicament treats a fungal infection.
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