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WO2024249983A1 - Dérivés de 2,8-dihydroxyquinoléine glucuronide présentant des propriétés améliorées destinés à être utilisés en tant qu'applications anticancéreuses, antivirales, antimicrobiennes et autres applications thérapeutiques - Google Patents

Dérivés de 2,8-dihydroxyquinoléine glucuronide présentant des propriétés améliorées destinés à être utilisés en tant qu'applications anticancéreuses, antivirales, antimicrobiennes et autres applications thérapeutiques Download PDF

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WO2024249983A1
WO2024249983A1 PCT/US2024/032216 US2024032216W WO2024249983A1 WO 2024249983 A1 WO2024249983 A1 WO 2024249983A1 US 2024032216 W US2024032216 W US 2024032216W WO 2024249983 A1 WO2024249983 A1 WO 2024249983A1
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acid
beta
pharmaceutical composition
hydroxy
quinolinyl
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Daniel C. Carter
Gary E. WEST
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Westol LLC
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Westol LLC
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the presently disclosed subject matter relates in general to the use of 2,8-Di- hydroxyquinoline glucuronide derivatives, and more specifically to the use of an isolated metabolic breakdown product known as 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (referred to herein as “G2-8HQ” or “W1469”) in compositions and methods for the treatment of cancer and other therapeutic applications including antiviral, antimicrobial, and anti-inflammatory microbial treatments.
  • G2-8HQ 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid
  • the invention also relates to the use of another hydroxyquinoline derivative known as 2,8-quinolinediol (2-8HQ) which can also be used in the same manner as G2-8HQ to treat cancers and other ailments.
  • hydroxyquinoline glucuronide derivatives with similar chemistry are provided, including those hydroxyquinoline derivatives with glucose, carbohydrate, or other substitutions at the hydroxyquinoline positions 3-7 on the hydroxyquinoline ring as described herein. These compounds can be used individually, or in complexes with copper or other metals that enhance their therapeutic effectiveness, and/or in combinations with omega fatty acids or other phospholipids.
  • This family is known as the 8-hydroxyquinoline pharmacophore family, and in general, there has been some evidence that the use of metal ionophore/chelating compounds from this family may be useful as anti-cancer agents. See, e.g., Toyokuni 1996; Brewer 2000; Theophanides, 2002; Desoize. 2003; and Huang 2005, as identified later herein).
  • 8HQ 8- hydroxyquinoline
  • a drug for human use was developed that was a second generation 8HQ-type drug intended to be a successor to CQ, called PBT2, and this was tried for the treatment of Alzheimer’s and Huntington’s disease (Cherny 2012).
  • PBT2 a second generation 8HQ-type drug intended to be a successor to CQ
  • CQ and many 8HQ derivatives continue to be explored as new treatments for clinically relevant pathogens (see You 2018; Bednarz-Prashad 1983; Auld 1974; Olaleye 2011; Darby 2010; Tavares 2018; and Bohlmann 2018), including certain attempts dealing with cancer and neurodegenerative diseases (e.g., Schimmer WE341W:216306:577531:1:ALEXANDRIA 2012; Ayton 2015; Tavares 2020; Cherny 2012; Lannfelt 2008; Ritchie 2003; Adlard 2008; and Shi 2020).
  • the function is associated with the direct metal interference, such as in the inhibition of metalloprotease, and in others, the alteration appears to be in transition metal homeostasis or the creation of ROS (reactive oxidation species) such as due to free radical, oxidative stress.
  • ROS reactive oxidation species
  • CQs activity in this area appeared to be attributed to blocking viral attachment to ACE receptor required for viral spike protein mediated infection.
  • copper chelation did not appear to be required for the anti-viral function.
  • investigators in the area of 8HQ compounds continue to search for those compounds that will be effective in treatments for conditions such as cancers, but also can be safely used with limited or no harmful side effects.
  • glucose adduct would improve solubility, target cancer cells to a higher degree of specificity due to an overabundance of glucose transport receptors (GLUT) and similarly potentially enhancing transport across the blood brain barrier where these receptors are also abundant.
  • GLUT glucose transport receptors
  • the anaerobic metabolism and high dependence on glucose that characterizes most cancers is a phenomenon known as the “Warburg Effect” (see Vander Heiden 2009).
  • the glucose adduct functions as an inactive prodrug to be converted to the active 8HQ form by the hydrolysis of the glycosidic bond by beta-glucosidases in the cytoplasm of cancer cells.
  • compositions and methods are provided for treating cancer and other conditions that comprise as the active ingredient 2,8-Di-hydroxyquinoline glucuronide derivatives, and more specifically the metabolic byproduct 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (referred to herein as “G2-8HQ” and “W1469”).
  • the compound 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (which is also known as 2,8-Dihydroxyquinoline-beta-D- glucuronide) has the formula as shown below: G2-8HQ: 8- acid WE341W:216306:577531:1:ALEXANDRIA
  • G2-8HQ 8- acid WE341W:216306:577531:1:ALEXANDRIA
  • the invention also relates to the use of G2-8HQ, its stereoisomers and congeners, and other compounds with similar chemistry, such as those glucose or carbohydrate derivatives at positions 3-7 of the hydroxyquinoline ring. These compounds include those O-linked glucose or carbohydrate derivatives wherein the substitution is at the hydroxyquinoline positions 3-7 instead of the substitution at position 2 as in G2-8HQ.
  • compositions and methods are provided for treating cancer and other conditions that comprise using as the active ingredient 2,8-quinolinediol (referred to herein as “2-8HQ”).
  • 2-8HQ 2,8-quinolinediol
  • the formula for 2,8-quinolinediol is as shown below: This diol is also known as 2,8-dihydroxyquinoline (2-8HQ) and it is contemplated that this compound or its natural enantiomeric tautomers can also be utilized in accordance with the present invention.
  • both G2-8HQ and 2-8HQ may be used in compositions and methods for treating cancers and a number of ailments as described further herein.
  • an isolated compound is provided for use in treating cancer and other conditions, and that compound is 8-Hydroxy-2- quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) as shown above.
  • G2-8HQ 8-Hydroxy-2- quinolinyl beta-D-glucopyranosiduronic acid
  • the compound G2-8HQ is an obscure and long overlooked metabolic product found in the serum of many herbivores including ungulates such as goats, and which had never been considered or studied for therapeutic purposes.
  • this compound may be isolated or synthesized for use in treating cancers and other conditions such as viral or microbial infections, asthma, neurodegenerative disease, and/or inflammation and inflammatory conditions in various ailments.
  • a pharmaceutical composition which comprises 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • the 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid may be complexed with a chelating metal such as copper and other metals such zinc, iron, cobalt, rhodium, and platinum, among others that would be known by those of ordinary skill in the art to be able to form complexes with the hydroxyquinolines of the invention.
  • the complexing of G2-8HQ with copper or other chelating metals can greatly enhance the effect of the active compound in treating cancer and reducing cancerous tumors.
  • the G2-8HQ either alone or in the form of a copper or other metal complex as described above, may be further combined with a suitable fatty acid, such as an omega fatty acid.
  • Such fatty acids may be omega-3 fatty acids such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA) and WE341W:216306:577531:1:ALEXANDRIA docosahexaenoic acid (DHA), or omega-6 fatty acids such as linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), or any combination thereof.
  • omega-3 fatty acids such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA) and WE341W:216306:577531:1:ALEXANDRIA docosahexaenoic acid (DHA), or omega-6 fatty acids such as linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), or any combination thereof.
  • G2-8HQ may also be used along with another hydroxyquinoline, for example, 8-hydroxyquinoline (8HQ), and in certain embodiments, a pharmaceutical composition is provided that comprises 8-Hydroxy-2- quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • G2-8HQ 8-Hydroxy-2- quinolinyl beta-D-glucopyranosiduronic acid
  • omega-3 fatty acids examples include alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and examples of the omega-6 fatty acid include linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), or any combination thereof.
  • ALA alpha-linoleic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • omega-6 fatty acid examples include linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), or any combination thereof.
  • the active ingredients of the pharmaceutical compositions of the present disclosure for example 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (G2-8HQ) and as 2,8-dihydroxyquinoline (2-8HQ), will be utilized in treatments for cancer and other ailments including viral and other microbial infections, asthma, neurodegeneration, and inflammation.
  • G2-8HQ 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid
  • 2-8HQ 2,8-dihydroxyquinoline
  • the concentration of the hydroxyquinoline derivatives of the invention including 8-Hydroxy- 2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and as 2,8- dihydroxyquinoline (2-8HQ) will range from about 100uM to about 500 mM, and in WE341W:216306:577531:1:ALEXANDRIA other exemplary embodiments, this concentration may be in the range of about 300 ⁇ M to about 150 mM, from about 1 mM to about 50 mM, or from 1 mM to about 25 mM.
  • the active ingredients described above may be supplemented by other compounds including an additional hydroxyquinoline, such as 8-hydroxyquinoline (8HQ) and/or an omega fatty acid, and in all cases, results may be enhanced when the active ingredients are administered in the presence of a chelating metal such as copper.
  • an additional hydroxyquinoline such as 8-hydroxyquinoline (8HQ) and/or an omega fatty acid
  • a method for treating cancer comprises administering an effective amount of an active hydroxyquinoline derivative ingredient such as 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (G2-8HQ) or 2,8-dihydroxyquinoline (2-8HQ), and these compounds may be administered in the form of a pharmaceutical composition that includes a pharmaceutically acceptable vehicle, carrier, or excipient as would be readily known by those or ordinary skill in the art.
  • the active ingredients may be administered in any suitable form as would be determined by the doctor or clinician based on the circumstances and condition of the patient.
  • the administration may be any of a variety of suitable forms, including oral or parenteral administration, injection, intravenous (IV) administration, a suppository, topical administration, and/or in the form of a spray mist.
  • the hydroxyquinoline derivatives as described herein may be administered in the presence of a chelating metal such as copper or other suitable metal such as zinc, iron, cobalt, rhodium, platinum, etc.
  • a suitable chelating metal such as copper has been observed to enhance the therapeutic abilities of the active compounds as described herein.
  • the hydroxyquinoline derivatives as described herein may be administered in the presence of another hydroxyquinoline such as 8-hydroxyquinoline (8HQ) and/or an omega fatty acid such as an omega-3 fatty acid or an omega-6 fatty acid.
  • 8HQ 8-hydroxyquinoline
  • omega fatty acid such as an omega-3 fatty acid or an omega-6 fatty acid.
  • the omega-3 fatty acid is selected from the group consisting of alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), land the omega-6 fatty acid is selected from the group consisting of linoleic acid (LA), arachidonic acid (AA), and docosapentaenoic acid (DPA), or any combination thereof.
  • ALA alpha-linoleic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • LA linoleic acid
  • AA arachidonic acid
  • DPA docosapentaenoic acid
  • the hydroxyquinoline derivatives as described herein including 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and as 2,8-dihydroxyquinoline (2-8HQ) may be used in methods of treating a condition selected from the group consisting of viral infection, a microbial infection, asthma, neurodegeneration, and inflammation, Such methods will comprise administering an effective amount of the composition of claim 1 to a subject in need thereof.
  • the effectiveness of the active hydroxyquinoline ingredients may be enhanced by administering these agents in the presence of a chelating metal such as copper, zinc, iron, cobalt, rhodium, and platinum, or any other suitable chelating metal that would be well known to those of ordinary skill in the art.
  • the active hydroxyquinoline ingredients may also be administered along with other compounds such as 8-hydroxyquinoline (8HQ) and/or an omega fatty acid such as an omega-3 fatty acid or an omega-6 fatty acid.
  • a pharmaceutical composition for use in treating cancer and other ailments that comprises 8-Hydroxy-2- quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid and a WE341W:216306:577531:1:ALEXANDRIA pharmaceutically acceptable vehicle, excipient, or carrier.
  • G2-8HQ 8-Hydroxy-2- quinolinyl beta-D-glucopyranosiduronic acid
  • a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid and a WE341W:216306:577531:1:ALEXANDRIA pharmaceutically acceptable vehicle, excipient, or carrier.
  • the omega-3 fatty acid may be alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA), and the omega-6 fatty acid may be linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), or any combination thereof
  • a pharmaceutical composition is provided that comprises 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid or 2,8-dihydroxyquinoline (2-8HQ) and a chelating metal.
  • the chelating metal is copper, and in other embodiments, the metal may be any suitable metal including but not limited to zinc, iron, cobalt, rhodium, and platinum.
  • the concentration of the 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (G2-8HQ) or 2,8-dihydroxyquinoline (2-8HQ) used in the pharmaceutical compositions of the invention will range from about 100 ⁇ M to about 500mM, and in other exemplary embodiments, this concentration may be in the range of about 300 ⁇ M to about 150 mM, from about 1 mM to about 50mM, or from 1 mM to about 25 mM.
  • the active ingredients described above may be supplemented by other compounds including an additional hydroxyquinoline, such as 8-hydroxyquinoline (8HQ) and/or an omega fatty acid.
  • a method of treating cancer comprising administering an effective amount of the pharmaceutical composition comprising hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid or 2,8- dihydroxyquinoline (2-8HQ) and a chelating metal to a human or animal patient in need thereof.
  • Such administration may be in a variety of suitable forms including oral, rectal, parenteral, injection, intravenous (IV), suppository, topical, and spray/mist.
  • This pharmaceutical composition may also be administered in combination with another hydroxyquinoline such as 8HQ and/or an omega fatty acid.
  • WE341W:216306:577531:1:ALEXANDRIA a method for treating a variety of ailments such as a viral infection, a microbial infection, asthma, neurodegeneration, or an inflammatory condition that comprises administering an effective amount of the pharmaceutical composition comprising hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid or 2,8-dihydroxyquinoline (2-8HQ) and a chelating metal to a human or animal patient in need thereof.
  • Such administration may be in a variety of suitable forms including oral, rectal, parenteral, injection, intravenous (IV), suppository, topical, and spray/mist.
  • This pharmaceutical composition may also be administered in combination with another hydroxyquinoline such as 8HQ and/or an omega fatty acid.
  • another hydroxyquinoline such as 8HQ and/or an omega fatty acid.
  • one suitable hydroxyquinoline compound for use in treating cancer and other ailments such as viral and bacterial infections, asthma, neurodegeneration, and inflammation is 2,8-quinolinediol (2-8HQ).
  • the compound 2,8-quinolinediol is another metabolic breakdown product and is believed to be the result of intracellular conversion of G2-8HQ by keto-enol chemistry at neutral to low pH and/or the ⁇ glucosidase hydrolysis reaction wherein 2-8HQ is released.
  • 2-8HQ is also an active Cu+2/Zn+2 chelator and thus may be complexed with a chelating metal such as copper, zinc, or a number of other suitable metals that would be well known in the art.
  • 2,8-quinolinediol (2-8HQ). is used in the form of a pharmaceutical composition comprising 2,8-quinolinediol and a pharmaceutically acceptable vehicle, excipient, or carrier, and this pharmaceutical composition may also include a metal such as copper, zinc, or other suitable metals. Still further, this pharmaceutical composition may also comprise an omega fatty acid and or an additional hydroxyquinoline such as 8-hydroxyquinoline (8HQ).
  • the present invention comprises a pharmaceutical composition for use in treating cancer and other ailments where the pharmaceutical composition compromises 2,8-quinolinediol (2-8HQ) and a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • This composition may also include a metal that will form a chelate complex with the active ingredient, and the metal will be any suitable metal capable of forming such complexes, including but not limited to copper, zinc, iron, cobalt, rhodium, and platinum.
  • a method for treating cancer and other ailments comprising administering a pharmaceutical composition comprising 2,8-quinolinediol (2-8HQ) and a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid, along with a pharmaceutically acceptable vehicle, excipient, or carrier.
  • This composition may also include a metal that will form a chelate complex with the active ingredient, and the metal will be any suitable metal capable of forming such complexes, including but not limited to copper, zinc, iron, cobalt, rhodium, and platinum.
  • the metals may also be in their ionic form, as would be recognized by one of ordinary skill in the art.
  • treatment may be carried out in any suitable form, such as oral, rectal, parenteral, injection, intravenous (IV), suppository, topical, and a spray of mist, such as an inhaler.
  • the active ingredients may also be administered with an omega fatty acid such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), and/or docosapentaenoic acid (DPA), or any combinations thereof.
  • omega fatty acid such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), and/or docosapentaenoic acid (DPA), or any combinations thereof.
  • a method for treating a condition selected from the group consisting of a viral infection, a microbial infection, a parasitic infection, asthma, neurodegeneration, and inflammation comprises administering a pharmaceutical composition comprising 2,8-quinolinediol (2-8HQ) and a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid, along with a pharmaceutically acceptable vehicle, excipient, or carrier.
  • a pharmaceutical composition comprising 2,8-quinolinediol (2-8HQ) and a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid
  • This composition may also include a metal that will form a chelate complex with the active ingredient, and the metal will be any suitable metal capable of forming such complexes, including but not limited to copper, zinc, iron, cobalt, rhodium, and platinum.
  • the metals may also be in their ionic form, as would be recognized by one of ordinary skill in the art.
  • treatment may be carried out in any suitable form, such as oral, rectal, parenteral, injection, intravenous (IV), suppository, topical, and a spray of mist, such as an inhaler.
  • the active ingredients may also be administered with an omega fatty acid such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), and/or and ⁇ docosapentaenoic acid (DPA), or any combinations thereof.
  • omega fatty acid such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), and/or and ⁇ docosapentaenoic acid (DPA), or any combinations thereof.
  • a pharmaceutical composition complex for use in treating a condition selected from the group consisting of cancer, a viral infection, a microbial infection, asthma, neurodegeneration, and inflammation, said composition comprising 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) or 2,8-quinolinediol (2-8HQ) and a chelating metal.
  • the chelating metal may be any suitable metal such as copper, zinc, iron, cobalt, rhodium, and platinum.
  • a pharmaceutical composition comprising a glucuronic acid substituted 2,8-dihydroxy quinolone and a pharmaceutically acceptable vehicle, carrier, or excipient.
  • substitutions may take advantage of the unique properties of the hydroxyquinoline derivatives of the invention such as G2-8HQ, but also may include the positioning of additional unique glucose or carbohydrate derivatives at the 8HQ positions, 2-7.
  • Such compounds have the desired solubility and targeting and do not have metabolic activation and thus do not act as prodrugs.
  • compositions wherein the glucuronic acid substituted 2,8- dihydroxy quinolone is selected from the group consisting of 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-3-quinolinyl beta-D- glucopyranosiduronic acid, 8-Hydroxy-4-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-5-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-6-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-7-quinolinyl beta-D- glucopyranosiduronic acid, 2-beta-D-glucopyranosiduronic acid-5-chloro-7-iodo-8- hydroxyquinoline; 8-Hydroxy-2-quinolinyl beta-D-glucopyran
  • This process uses UDP- glucuronosyltransferase to create the soluble metabolic product glucuronide 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) of the present invention.
  • G2-8HQ 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid
  • 2,8HQ which is otherwise insoluble in aqueous systems, is most likely solubilized by albumin and highly bound, and is then off loaded by albumin in the liver to create G2,8HQ which is now soluble and freely circulating.
  • one possible embodiment of the invention would be to administer 2,8HQ (a very inexpensive precursor) either orally, or by precomplexation with albumin as an alternate treatment approach, where the desired active targeting metabolite is created by glucuronidation in the liver creating the glucuronide derivative G2-8HQ.
  • a glucopyranosiduronic acid such as G2-8HQ is provided that is substituted with a different sugar at the 2- position, and this compound may be used in the form of a pharmaceutically acceptable composition that also contains a pharmaceutically acceptable vehicle, excipient, or carrier.
  • the different sugar at the 2-position is selected from the group consisting of galactose, glucose, fructose, sucrose, and trihalose.
  • a pharmaceutical composition is provided that comprising 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) modified so that an O-linked sugar is at a position other than at position 8, and a WE341W:216306:577531:1:ALEXANDRIA pharmaceutically acceptable vehicle, excipient, or carrier.
  • a pharmaceutical composition is provided that comprises a glucuronic acid substituted 2,8-dihydroxy quinolone and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • the glucuronic acid derivative is 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid, and in other embodiments, the glucuronic acid derivative is 8-Hydroxy-quinolinyl beta-D-glucopyranosiduronic acid.
  • these compounds may also be utilized in the form of a complex with a suitable metal such as copper or other metals, and these compositions will also be useful in accordance with the methods of treatment as described herein.
  • the hydroxyquinolines of the invention as described herein may be obtained by suitable synthesis methods as described in previous articles relating to the research on these compounds as referred to herein.
  • the compounds of the invention that are metabolic products can be isolated from the serum of ungulates such as goats and numerous other hooved mammals, using methods of separation and isolation known in the art.
  • the pharmaceutical compositions containing G2-8HQ, 2- 8HQ and the other hydroxyquinoline compounds as described in this disclosure may be used in methods of treating cancer and the other ailments as described herein. These compounds and the compositions containing them may also be used along with a metal to form chelate complexes that enhance the therapeutic effect of these compounds.
  • These pharmaceutical compositions may also contain phospholipids such as an omega fatty acid.
  • compositions and methods are provided for treating cancer and other conditions that comprise as the active ingredient 2,8-Di-hydroxyquinoline glucuronide derivatives, and more specifically the metabolic WE341W:216306:577531:1:ALEXANDRIA byproduct 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (referred to herein as “G2-8HQ” and “W1469”).
  • the 8-Hydroxyquinolines in general represent a family of molecules highly studied and applied in the field of inorganic and bioinorganic chemistry. They are bi and tridentate metal-chelating compounds known to exhibit a spectrum of potent biological properties which include anti-viral, antimicrobial and anti- cancer activities.
  • the isolation, identification, synthesis, and characterization of several endogenous small molecules in this family for their use in methods of treating cancer As indicated below, certain of these small molecules of the invention identified from the serum plasma fraction of goats have been shown to exhibit extraordinary in vitro and in vivo activity against a large number of cancers, microbes (e.g., mycobacteria tuberculosis, Cryptococcus) and viruses (e.g., HIV, rotavirus, SARS, COVID 19, etc.)
  • two of the 8- hydroxyquinols identified with the potential for use in anti-cancer and other therapeutic treatments are 8-hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (identified here as G2-8HQ), a metabolic derivative of 8-hydroxyquinoline (8HQ), and 2,8– quinolinediol (identified herein as 2-8HQ).
  • the IC50 for G2-8HQ against the RL non-Hodgkin’s lymphoma cell line in the presence of copper increased by more than 1000-fold (from >500uM - Cu +2 to IC500.468 ⁇ M + Cu +2 ), whereas the same additional presence of copper only increased the activity of 8HQ by 9-fold (IC50 WE341W:216306:577531:1:ALEXANDRIA 0.06 ⁇ M + Cu +2 ).
  • G2-8HQ is utilized along with copper or other metals so as to maximize its ability to be used as an anti-cancer and an anti-microbial agent
  • G2-8HQ is the only drug candidate that shows an absence of cytotoxicity (no measurable IC50 in standard drug concentration ranges).
  • G2-8HQ in treating cancer and other conditions will have a greater safety margin (Therapeutic Index) than any previously reported pro-drug glucose or glucuronide derivatives of 8HQ and its congeners, e.g., clioquinol
  • G2-8HQ exhibits comparable or superior anti-proliferative activity than the prior compounds.
  • Significantly lower toxicity to non-malignant tissues may allow for more extended treatment protocols thereby increasing the likelihood of a favorable clinical outcome.
  • beta-glucosidase is not required for the activity of G2-8HQ.
  • the G2-8HQ complex with copper or other metals remains uncharacteristically highly soluble in aqueous solutions, which further its effectiveness and safety as an anti-cancer, anti- microbial, anti-viral, and anti-inflammatory composition.
  • the compound G2-8HQ is provided for use as an anti- cancer, anti-viral, anti-bacterial, anti-parasitic, anti-fungal agent with enhanced and highly desirable efficacy, but also enhanced safety and clinical administrative characteristics.
  • G2-8HQ represents the first direct ring modified o-linked glucose or glucuronic acid (any sugar) at the 2 position of G2-8HQ to be used in any therapeutic platform.
  • G2-8HQ was merely noted as one of many metabolic products found in the serum and tissues of ungulates and birds presumably WE341W:216306:577531:1:ALEXANDRIA of dietary and gut microbial origin, and thus there has been no focus on this compound for any therapeutic properties.
  • G2-8HQ has a unique desirable solubility and prodrug-like properties with the further ability to be used in cancer applications to provide improved tumor partitioning.
  • G2-8HQ has powerful anticancer activity against all cell lines tested and further shows the biological activity is further enhanced through copper or other metal chelation.
  • G2-8HQ can be utilized by chelating this compound with copper or other metals such as Zinc (Zn), Iron (Fe), Cobalt (Co), Rhodium (Rh), Platinum (Pt) and others as described further herein.
  • Zinc (Zn) Zinc
  • Iron (Fe) Iron
  • Cobalt Co
  • Rhodium Rh
  • Platinum Pt
  • G2-8HQ other compounds employed in the present disclosure include those quinoline compounds that add additional unique glucose or carbohydrate derivatives at the positions 2-7 of 8HQ, which will have similar properties to G2-8HQ wherein the glucose or other sugar is at the 8 position.
  • Such compounds also have the desired solubility and targeting, and also do not have the requirement of metabolic activation (i.e., they are not prodrugs).
  • the use of the compounds of the present invention individually or in combination with copper, other metals, and/or omega fatty acids as described herein are thus useful in compositions, methods, and uses related to anti-cancer, anti-inflammatory, anti-viral, and anti-microbial treatments.
  • other compounds are provided in which have a substitution of other sugars at the 2 position WE341W:216306:577531:1:ALEXANDRIA (such as galactose, glucose, fructose, sucrose, trihalose, etc.) and any congeners of such sugar-2-8HQ forms thereof are also provided in accordance with the invention.
  • the biological basis for anticancer and antiviral activity present in the sera of selected goats has been determined by assessing two hydroxyl quinoline compounds, 8-hydroxyquinoline (8HQ) and 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (G2-8HQ).
  • G2-8HQ 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid
  • additional compounds such as omega fatty acids, or in combination with chelating metals such as copper
  • chelating metals such as copper
  • the 2-hydroxy however has the unique property among all 8-hydroxy WE341W:216306:577531:1:ALEXANDRIA quinolone frame derivatives in its inherent keto-enol chemistry.
  • Prior testing of the 8HQs has focused on prodrug forms where the release of the aglycone drug form must be enzymatically accomplished by beta-glucosidase.
  • this is another problem that is overcome by the present disclosure.
  • G2-8HQ of the present invention which is chemically stable at neutral or physiological pH in the plasma, the reactive chemistry/instability of the glucuronide at position 2 provides a potentially advantageous intracellular pathway at acidic cytosolic pH, to release or “kick-off” the sugar moiety.
  • G2-8HQ can chelate copper without enzymatic or keto-enol hydrolysis.
  • the high standard deviations observed in the present results of in vitro screening as described herein disappears, once again confirming that the G2-8HQ antiproliferative activity makes particularly good use of copper when added, and that the copper complex represents the activated form.
  • G2-8HQ in complex with copper can be administered with the glucuronic acid/glucose-based targeting intact, unlike any of the prior art described by Monson and Oliveri.
  • G2-8HQ remains highly aqueous soluble.
  • none of the extensive 8HQ studies in the prior art examined the special O-linked chemistry of the 8-hydroxyquinoline frame as embodied in the present invention. And indeed there have been no reported studies regarding any isolation of antiproliferative or other potential therapeutic studies of the 2,8HQ parent compound or G2-8HQ.
  • the hydroxyquinoline compounds that are useful in the present invention may include others involving the WE341W:216306:577531:1:ALEXANDRIA same keto-enol chemistry that can be applied to a variety of sugars, as well as congeners of the 8-hydroxy frame, including simple congeners of the main frame such as halide methyl, alcohol, carboxylic acids, etc., and these are provided by virtue of the present invention as well. Still other derivatives of hydroxyquinolines are provided in the present invention, and these have also shown properties indicative of those described herein for G2-8HQ. BRIEF DESCRIPTION OF THE DRAWING FIGURES Figure 1.
  • Cytotoxicity of WT1469 (G2-8HQ) against PANC-1 pancreatic cancer; in the presence of Cu +2 ions. Note the wide standard deviation at 1 and 0.5 ⁇ M indicating that in some % of the screens all the cancer cells were killed at these concentrations. The reason for the large standard deviations for W1469 + Cu is discussed vide infra. Figure 6. Cytotoxicity of WT1469 (G2-8HQ) against SU.86.86: a new adoptive pancreatic cell for immunotherapy studies in the presence of Cu +2 ions. Note the wide standard deviation at 1 and 0.5 ⁇ M indicating that in some % of the screens all the cancer cells were killed at these concentrations.
  • Figure 14 Biological Activity of 8-hydroxyquinoline (8HQ).
  • Figure 15 (A) 8-Hydroxyquinoline (8HQ); (B) Copper complex of 8HQ with a metal:ligand ratio of 1:1; (C) Copper complex of 8HQ with a metal:ligand ratio of 1:2; (D) Nitroxoline; (E) Clioquinol; and (F) 8-Hydroxyquinoline-2-cqrboxylic acid (HCA).
  • Figure 23 This is a photo of a patient in one of the clinical studies of the effectiveness of the treatment and compositions of the disclosure that was taken prior to treatment.
  • Figure 24 This is a photo of a patient in one of the clinical studies of the effectiveness of the treatment and compositions of the disclosure that was taken following the course of a three-week treatment.
  • Figure 25 This is a photo of a patient in another one of the clinical studies of the effectiveness of the treatment and compositions of the disclosure that was taken prior to treatment.
  • Figure 26 This is a photo of a patient in another one of the clinical studies of the effectiveness of the treatment and compositions of the disclosure that was taken following one-week treatment.
  • compositions and methods are provided for treating cancer and other conditions that comprise as the active ingredient 2,8-Di- hydroxyquinoline glucuronide and its derivatives, and more specifically the metabolic intermediate byproduct 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (referred to herein as “G2-8HQ” and “W1469”).
  • the compound 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (which is also known as 2,8-Dihydroxyquinoline- beta-D-glucuronide) has the formula as shown below:
  • the invention also relates to the use of G2-8HQ, its stereoisomers and congeners, and other compounds with similar chemistry, such as those glucose or carbohydrate derivatives at positions 3-7 of the hydroxyquinoline ring. These compounds include those O-linked glucose or carbohydrate derivatives wherein the substitution is at the hydroxyquinoline positions 3-7 instead of the substitution at position 2 as in G2-8HQ.
  • compositions and methods are provided for treating cancer and other conditions that comprise using as the active ingredient 2,8-quinolinediol (2-8HQ).
  • 2,8-quinolinediol also known as 2,8-dihydroxyquinoline
  • the formula for 2,8-quinolinediol is as shown below: As described or its natural enantiomeric tautomers, stereoisomers, or congeners can also be utilized in accordance with the present invention in compositions and methods used for treating cancers and a number of ailments as described further herein.
  • the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
  • any specific amount within that range is considered part of the invention.
  • a range is given in mg/kg, this means that the range includes any individual amount within the range, WE341W:216306:577531:1:ALEXANDRIA for example if a range is provided as “10 ⁇ M to 100 ⁇ M” , all ranges within the parameter of that range are considered disclosed, and the range covers all individual amounts within that range, e.g., in 0.1 or 0.5 intervals. Accordingly, the inclusive range of “10 to 100” would include, for example, each 0.1 interval, such that the range would include a lower limit of about 10.1, 10,2, etc. in addition to about 10.0, and the upper range would include an upper limit of 99.9, 99.8, 99.7, etc., in addition to about 100.0.
  • the specific amount used may include any specific amount in the range, such as in 0.1 ⁇ M increments, so that amounts of 10.0, 10.1, 10.2, 10.3 and so forth up and including through 100.0 could be administered within the range of from about 10 to 100, and similarly for all ranges in accordance with the present invention.
  • the active compounds of the invention may be administered in the form of a pharmaceutical composition that may also include a pharmaceutically acceptable vehicle, carrier, or excipient.
  • the term “pharmaceutical vehicle, carrier or excipient” or “pharmaceutically acceptable vehicle, carrier or excipient” may refer to any of a wide variety of materials known for general usage in delivering a pharmaceutical agent or agents to a patient.
  • Non-limiting examples of such materials include any solid forms that can be utilized in any suitable form of administration, such as oral administration, injection, intravenous (IV), suppository, topical, and spray/mist.
  • the pharmaceutical compositions of the invention may also include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • the active hydroxyquinoline derivatives of the invention are used in methods of treating cancer and other conditions, such as viral infections, microbial infections, asthma, neurodegeneration, and inflammation.
  • the active ingredients of the invention will be administered to a subject in need thereof in an effective amount.
  • the term “effective amount” refers to an amount that is sufficient to achieve the desired treatment result or to have an effect on the targeted condition being treated.
  • an “effective amount” or a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms being targeted, but in such a manner as to achieve that objective but also reduce or eliminate the possibility of adverse side effects as would be recognized by those of ordinary skill in the art.
  • the specific therapeutically effective dose level for use in the treatment of any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts.
  • the terms “subject” or “subject in need thereof” or “patient” or “patient in need thereof” refer to a target of administration, which optionally displays symptoms related to a particular disease, pathological condition, disorder, or the like.
  • the subject of the herein disclosed methods can be a human or animal patient, including mammals and other vertebrates in need of such treatment.
  • the term subject or patient does not denote a particular age or sex and generally refers to a human or animal subject needing or receiving said treatment.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (G2-8HQ) and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • G2-8HQ 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid
  • a pharmaceutically acceptable vehicle, excipient, or carrier may refer to any of a wide variety of materials known for general usage in delivering a pharmaceutical agent or agents to a patient.
  • Non-limiting examples of such materials include any solid forms that can be utilized in any suitable form of administration, such as oral administration, injection, intravenous (IV), suppository, topical, and spray/mist forms.
  • the G2-8HQ of the invention may be administered alone or in the presence of a chelating metal, such as copper, of the ionic form of the chelating metal.
  • a chelating metal such as copper
  • the presence of copper appears to enhance the anti-cancer ability and other therapeutic properties of G2-8HQ, there will normally be sufficient copper in the blood serum so that G2-8HQ will have suitable biological activity against cancer when administered to a subject in need thereof.
  • the metal can be selected from the group consisting of copper, zinc, iron, cobalt, rhodium, and platinum. Further metals such as arsenic, antimony, gold, and vanadium could also be used in situations wherein the potential toxicity is reduced or eliminated.
  • the G2-8HQ pharmaceutical composition as described herein may also include a suitable phospholipid such as an omega fatty acid.
  • the omega fatty acid used may be an omega-3 fatty acid and/or an omega-6 fatty acid.
  • the omega-3 fatty acid may be selected from the group consisting of alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and combinations thereof
  • the omega-6 fatty acid may be selected from the group consisting of linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), and combinations thereof.
  • the G2-8HQ pharmaceutical composition can also include a hydroxyquinoline such as 8-hydroxyquinoline (8HQ).
  • the level of the G2-8HQ used in the present compositions will normally be that amount considered to be an effective amount against a particular condition of a patient in need of treatment thereof.
  • the term “effective amount” refers to an amount that is sufficient to achieve the desired treatment result or to have an effect on the targeted condition being treated.
  • an “effective amount” or a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms being targeted, but in such a manner as to achieve that objective but also reduce or eliminate the possibility of adverse side effects as would be recognized by those of ordinary skill in the art.
  • the specific therapeutically effective dose level for use in the treatment of any particular patient will depend upon a variety of factors that can be determined by the doctor or other clinician and can include the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts.
  • the G2-8HQ compositions of this disclosure may contain G2-8HQ at a concentration in the range of about 100 WE341W:216306:577531:1:ALEXANDRIA ⁇ M to about 500 mM.
  • this concentration may be in other suitable ranges, such as from about 300 ⁇ M to about 150 mM, from about 1 mM to about 50 mM, or from about 1 mM to about 25 mM.
  • a method for treating cancer comprises administering an effective amount of a pharmaceutical composition comprising G2-8HQ and a pharmaceutically acceptable vehicle, carrier, or excipient to a subject in need thereof.
  • this administration can be in a number of suitable ways, including oral administration, injection, intravenous (IV), suppository, topical, and spray/mist, as would be determined by a doctor or other clinician based on the specific circumstances of the patient or subject being treated.
  • the G2-8HQ pharmaceutical composition can also comprise or be administered with a chelating metal such as copper, zinc, iron, cobalt, rhodium, or platinum. In certain embodiments, the metal will be copper.
  • this pharmaceutical composition may also include or be administered with a phospholipid such as an omega fatty acid.
  • the omega fatty acid may be an omega 3 fatty acid or an omega 6 fatty acid, and the omega fatty acids may be selected from the group consisting of alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), ⁇ docosapentaenoic acid (DPA), and combinations thereof.
  • ALA alpha-linoleic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • LA linoleic acid
  • AA arachidonic acid
  • DPA ⁇ docosapentaenoic acid
  • a method for treating a condition selected from the group consisting of viral infection, a WE341W:216306:577531:1:ALEXANDRIA microbial infection, asthma, neurodegeneration, such as Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or Parkinson's disease, and inflammation comprising administering an effective amount of a pharmaceutical composition comprising G2-8HQ and a pharmaceutically acceptable vehicle, carrier, or excipient to a subject in need thereof.
  • this administration can be in a number of suitable ways, including oral administration, injection, intravenous (IV), suppository, topical, and spray/mist, as would be determined by a doctor or other clinician based on the specific circumstances of the patient or subject being treated.
  • the pharmaceutical composition comprising G2-8HQ and a pharmaceutically acceptable vehicle, carrier, or excipient is administered along with a chelating metal.
  • the chelating metal is selected from the group consisting of copper, zinc, iron, cobalt, rhodium, and platinum.
  • this pharmaceutical composition may also be administered along with a phospholipid such as an omega fatty acid.
  • the omega fatty acid may be an omega 3 or 6 fatty acid such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), and/or docosapentaenoic acid (DPA), and/or combinations thereof.
  • omega 3 or 6 fatty acid such as alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), and/or docosapentaenoic acid (DPA), and/or combinations thereof.
  • a pharmaceutical composition comprises 8-Hydroxy-2-quinolinyl beta- D-glucopyranosiduronic acid (G2-8HQ) and a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • G2-8HQ 8-Hydroxy-2-quinolinyl beta- D-glucopyranosiduronic acid
  • a compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an omega-6 fatty acid and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • a pharmaceutical composition that comprises 8-Hydroxy-2-quinolinyl beta- WE341W:216306:577531:1:ALEXANDRIA D-glucopyranosiduronic acid and a chelating metal, and this chelating metal can be copper or any other suitable chelating metal, including but not limited to zinc, iron, cobalt, rhodium, and platinum.
  • the pharmaceutical compositions comprise G2-8HQ as the active ingredient, and such compositions can be prepared using an effective amount of G2-8HQ that would be needed to treat a particular condition.
  • the 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid is at a concentration in the composition in the range of about 100 ⁇ M to about 500mM.
  • the amount of the G2-8HQ may also be in the range of from 300 ⁇ M to about 150 mM, from about 1 mM to about 50 mM, or from about 1 mM to about 25 mM.
  • an effective amount of G2-8HQ is administered to a subject in need thereof, and such effective amounts may include concentrations in the ranges as described herein.
  • the effective amounts of the active ingredients may be administered to a subject or patient in need thereof by any suitable method that would be determined by a doctor or clinician under the particular circumstances, and such administration may be selected from the group consisting of oral administration, injection, intravenous (IV), suppository, topical, and a spray/mist.
  • IV intravenous
  • the pharmaceutical compositions comprising G2-8HQ and other compounds of the disclosure may be administered along with phospholipids such as omega fatty acids.
  • omega fatty acids can be selected from the group consisting of alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), and combinations thereof.
  • ALA alpha-linoleic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • LA linoleic acid
  • AA arachidonic acid
  • DPA docosapentaenoic acid
  • a method of treating a condition selected from the group consisting of a viral infection, a microbial infection, asthma, neurodegeneration, and inflammation comprising administering an effective amount of the composition comprising 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and a chelating metal to a subject in need thereof.
  • the chelating metal is selected from the group consisting of copper, zinc, iron, cobalt, rhodium, and platinum.
  • the composition to be administered in this method may also comprise an omega fatty acid or other phospholipid.
  • another hydroxyquinoline compound in accordance with this disclosure comprises 2,8-quinolinediol (2-8HQ) which may be utilized in the therapeutic methods as described herein.
  • a pharmaceutical composition is also provided which comprises 2,8-quinolinediol (2-8HQ) and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • the pharmaceutical composition utilizing 2-8HQ as the active ingredient may also comprise a chelating metal such as copper, or other common chelating metals including but not limited to zinc, iron, cobalt, rhodium, and platinum.
  • this composition may also comprise an omega fatty acid, such as an omega-3 fatty acid and/or an omega-6 fatty acid.
  • Such fatty acids may be selected from the group consisting of alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), arachidonic acid (AA), docosapentaenoic acid (DPA), and combinations thereof. Still further, an additional hydroxyquinoline such as 8-hydroxyquinoline (8HQ) may also be added to this composition.
  • ALA alpha-linoleic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • LA linoleic acid
  • AA arachidonic acid
  • DPA docosapentaenoic acid
  • 8HQ 8-hydroxyquinoline
  • a pharmaceutical composition that comprises 2,8-quinolinediol (2-8HQ) and another compound selected from the group consisting of 8HQ, an omega-3 fatty acid, and an WE341W:216306:577531:1:ALEXANDRIA omega-6 fatty acid, and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • a composition may further comprise a chelating metal such as copper, zinc, iron, cobalt, rhodium, and/or platinum.
  • a pharmaceutical composition is provided comprising 2,8- quinolinediol (2-8HQ) and a chelating metal.
  • a method of treating cancer comprises administering an effective amount of this composition to a patient or subject in need thereof.
  • administration may be carried out in a number of suitable ways, including oral administration, injection, intravenous (IV), suppository, topical, and/or by the use of a spray or mist, such as would be administered in an inhaler or other means of inhalation.
  • the 2-8HQ compound may also be administered with a suitable chelating metal.
  • the metals used along with the active compounds of the disclosure may be used in the form of ions, such as copper ions, zinc ions, iron ions, cobalt ions, rhodium ions, and/or platinum ions.
  • these 2-8HQ pharmaceutical compositions may also include a phospholipid such as an omega fatty acid.
  • the G2-8HQ and 2-8HQ compounds of the present invention may be used in the therapeutic methods as described herein. For example, a method of treating cancer is provided which comprises administering an effective amount of G2-8HQ and/or 2-8HQ to a patent or subject in need of treatment thereof.
  • the G2-2HQ and 2-8HQ compounds of the present invention may be used in a method of treating a condition selected from the group consisting of a viral infection, a microbial infection, a parasitic infection, asthma, a neurodegenerative condition, and inflammation that comprises WE341W:216306:577531:1:ALEXANDRIA administering an effective amount of G2-@HQ and/or 2-8HQ to a patient or subject in need thereof.
  • a condition selected from the group consisting of a viral infection, a microbial infection, a parasitic infection, asthma, a neurodegenerative condition, and inflammation that comprises WE341W:216306:577531:1:ALEXANDRIA administering an effective amount of G2-@HQ and/or 2-8HQ to a patient or subject in need thereof.
  • a condition selected from the group consisting of a viral infection, a microbial infection, a parasitic infection, asthma, a neurodegenerative condition, and inflammation that comprises WE341W:216306:577531:1:
  • the active G2-8HQ and 2-8HQ compounds may be administered with a chelating metal and/or a phospholipid such as an omega fatty acid.
  • a pharmaceutical composition complex is provided for use in treating a condition selected from the group consisting of cancer, a viral infection, a microbial infection, asthma, neurodegeneration, and inflammation comprising a glucuronic acid substituted 2,8- dihydroxy quinolone such as an 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and/or 2,8-quinolinediol (2-8HQ) in a pharmaceutically acceptable vehicle, carrier, or excipient, and such a composition may also include a chelating metal to form the complex.
  • a glucuronic acid substituted 2,8- dihydroxy quinolone such as an 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and/or 2,8-quinolinedi
  • a pharmaceutical composition complex for use in treating a condition selected from the group consisting of cancer, a viral infection, a microbial infection, asthma, neurodegeneration, and inflammation comprising a glucuronic acid substituted 2,8-dihydroxy quinolone such as an 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and/or 2,8- quinolinediol (2-8HQ) in a pharmaceutically acceptable vehicle, carrier, or excipient, and such a composition may also include a chelating metal.
  • a glucuronic acid substituted 2,8-dihydroxy quinolone such as an 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and/or 2,8- quinolinediol (2-8HQ) in a pharmaceutically acceptable vehicle, carrier, or excipient, and such a composition may also include a chelating metal.
  • the glucuronic acid substituted 2,8-dihydroxy quinolone may include any of a number of suitable compounds that contain substitutions at other positions on the hydroxyquinoline ring.
  • Such glucuronic acid substituted 2,8-dihydroxy quinolone compounds may be selected WE341W:216306:577531:1:ALEXANDRIA from the group consisting of 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-3-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-4-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-5-quinolinyl beta-D- glucopyranosiduronic acid, 8-Hydroxy-6-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-7-quinolinyl beta-D-glucopy
  • a glucuronic acid derivative compound selected from the group consisting of 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid, 8- Hydroxy-3-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-4-quinolinyl beta- D-glucopyranosiduronic acid, 8-Hydroxy-5-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-6-quinolinyl beta-D-glucopyranosiduronic acid, 8-Hydroxy-7- quinolinyl beta-D-glucopyranosiduronic acid, 2-beta-D-glucopyranosiduronic acid-5- chloro-7-iodo-8-hydroxyquinoline; 8-Hydroxy-2-quinolinyl beta-D-glucopyranoside, 8-
  • compositions may also comprise a chelating metal and/or other materials such as 8HQ and/or phospholipids such as an omega fatty acid.
  • a pharmaceutical composition is provided that comprises 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (G2-8HQ) that is substituted with a different sugar at the 2- position, and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • the sugar that is substituted can be any suitable sugar, including but not limited to galactose, glucose, fructose, sucrose, and trihalose.
  • a pharmaceutical composition comprising 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) modified so that an O-linked sugar is at a position other than at position 2, and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • the compositions may also include a chelating metal, and/or a phospholipid such as an omega fatty acid.
  • a pharmaceutical composition is provided that comprises a 2,8-dihydroxy quinolone glucuronic acid derivative and a pharmaceutically acceptable vehicle, carrier, or excipient.
  • the glucuronic acid derivative is 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid
  • the glucuronic acid derivative is 8-Hydroxy-quinolinyl beta-D-glucopyranosiduronic acid.
  • these compositions can be used in effective amounts in methods of treating a condition selected from the group consisting of cancer, a viral infection, a microbial infection, asthma, neurodegeneration, and inflammation. WE341W:216306:577531:1:ALEXANDRIA
  • the present compositions can be prepared through synthesis of the active ingredients as described herein.
  • G2-8HQ, 2-8HQ and the other hydroxyquinoline compounds of the invention can be obtained by isolation of these compounds from the serum of an ungulate and combining G2-8HQ with a pharmaceutically acceptable vehicle, carrier, or excipient.
  • these compounds are generally intermediate metabolic products found in the serum of ungulates such as goats, and these compounds may be isolated as described herein or by other methods known in the art of isolating compounds from blood and/or serum.
  • a method for use in treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid (G2-8HQ) and a pharmaceutically acceptable vehicle, excipient, or carrier.
  • the 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid is chelated with a metal.
  • the 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid and the other suitable compounds of the invention may be administered along with serum plasma albumin, such as human serum albumin.
  • a pharmaceutical composition for use in treating cancer comprising 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid (G2-8HQ) and a pharmaceutically acceptable vehicle, excipient, or carrier:
  • the 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid may be chelated with a metal, and additionally, an omega fatty acid may also be added.
  • WE341W:216306:577531:1:ALEXANDRIA The active compounds and pharmaceutical compositions as described herein thus have suitable therapeutic properties so they can be utilized in a variety of therapeutic uses.
  • an isolated 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid for the treatment of cancer in a human or animal subject in need thereof.
  • the isolated 8-Hydroxy-2-quinolinyl beta-D- glucopyranosiduronic acid may be used in the form of a pharmaceutical composition wherein it is used along with a pharmaceutically acceptable vehicle, carrier, or excipient.
  • an isolated 8-Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid for treatment of a condition selected from the group consisting of a viral infection, a microbial infection, a parasitic infection, asthma, neurodegeneration, and inflammation.
  • an effective amount of the isolated 8-Hydroxy-2- quinolinyl beta-D-glucopyranosiduronic acid is used with a pharmaceutically acceptable vehicle, carrier, or excipient, and in this composition, the isolated 8- Hydroxy-2-quinolinyl beta-D-glucopyranosiduronic acid may be used with a chelating metal.
  • an isolated 2,8-quinolinediol (2-8HQ) is provided for the treatment of cancer in a human or animal subject in need thereof.
  • the isolated 2-8HQ may be used in the form of a pharmaceutical composition wherein it is used along with a pharmaceutically acceptable vehicle, carrier, or excipient.
  • an effective amount of the isolated 2-8HQ is used with a pharmaceutically acceptable vehicle, carrier, or excipient, and in this composition, the isolated 2-8HQ may be used along with a chelating metal.
  • Formulations Summary (1) Topical Applications All of the examples below would contain from about 0.5 to 4mg/ml of W1469. Topical Example 1. Wherein the W1469 is dissolved in ethanol or aqueous buffered solutions thereof. Topical Example 2. More specifically, an aqueous ethanol (20% to 60%) buffered 0.05M to 0.2 M (HEPPES or PBS) from about pH 6.5 to 8.5, more specifically pH 7.4.
  • Topical Example 3 WE341W:216306:577531:1:ALEXANDRIA Same as Example 1 with the addition of recombinant human serum albumin and/or sucrose/glucose at concentrations of 10 to 20 mg/ml as an excipient to aid in drug stabilization and skin penetration.
  • Topical Example 4. Wherein the W1469 is dissolved in DMSO or aqueous buffered solutions thereof.
  • Injectable Envisioned routes of administration include by conventional means and practice of those skilled in the art of establishing safety and efficacy and (formulation) and using drug delivery methodologies common to those practices (IV, IP, etc.).
  • the drug may be incorporated in a sterile buffered low endotoxin PBS or other biologically compatible isotonic solution such as albumin.
  • EXAMPLES The presently-disclosed subject matter is further illustrated by the following specific but non-limiting examples. Some of the following examples are prophetic, notwithstanding the numerical values, results and/or data referred to and contained in the examples.
  • microbes such as mycobacteria tuberculosis and Cryptococcus
  • the IC50 for G2-8HQ against the RL non-Hodgkin’s lymphoma cell line in the presence of copper increased by more than 1000-fold (from >500uM Cu +2 to IC50 0.468 ⁇ M + Cu +2 ), and for 8HQ by 9-fold (IC500.06 ⁇ M + Cu +2 ), but these tests showed that G2-8HQ appeared to possess higher activity against cancer cell lines than 8HQ.
  • G2-8HQ Unlike previous pro-drug glucose or glucuronide derivatives which require enzymatic activation via ⁇ -glucosidase to release the active aglycone form, beta -glucosidase is not required by G2-8HQ. Additionally, G2-8HQ copper complex remains uncharacteristically, highly soluble in aqueous solutions. As evidenced by these results, G2-8HQ appears to be useful as an anti-cancer agent with greater solubility and a greater safety margin than what has been previously possible using 8HQ. Moreover, G2-8HQ contains a validated tumor targeting functionality which limits board systemic exposure and thus further improves both the safety and efficacy.
  • omega-3 polyunsaturated fatty acids included alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the omega-6 polyunsaturated fatty acids included linoleic acid (LA), arachidonic acid (AA), and ⁇ docosapentaenoic acid (DPA).
  • ALA alpha-linoleic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • omega-6 polyunsaturated fatty acids included linoleic acid (LA), arachidonic acid (AA), and ⁇ docosapentaenoic acid (DPA).
  • Table 1 A selection of top differences in phospholipids between two animals.
  • G2-8HQ has been identified, but not quantified or subject to further study relating to anticancer and other therapeutic properties.
  • G2- 8HQ is a metabolic intermediate product that has been identified in a variety of animals including poultry and rabbits in addition to ungulates such as horses, sheep, cattle, bison, deer, goats and swine.
  • G2-8HQ The principal locations for G2-8HQ appear to be in isolates from the blood, kidney and liver, and it is assumed that diet is the source for the primary compounds from which G2-8HQ is ultimately formed. For example, studies have identified 8HQ in the roots of some types of invasive knapweed plants, and this leads to the formation of 2-8HQ, a product of bacterial fermentation in the rumen in the case of ungulates.2-8HQ is absorbed into the blood stream where it is further metabolized in the liver by UDP-glucuronosyltransferase (UDPGT) to yield G2- 8HQ.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • 2-8HQ The presumed bacterial digestive origin of 2-8HQ is supported by its identification as a metabolite of 8HQ in the culture medium of at least one bacteria, Pseudomonas stutzeri. These compounds appear to be significantly elevated or induced in biologically active animal serum, and G2-8HQ has also been reported as one of the metabolic biomarkers for Peroxisome proliferator-activated receptor ⁇ (PPAR ⁇ ) expression and activation in mice (Zhen 2007). The plasma concentrations of these compounds have not yet been determined quantitatively, but can be estimated in a range of approximately 100 ⁇ M to 5 mM based on the limitations of GC mass spec instrumentation utilized to identify them.
  • EXAMPLE 2 Characterization of Anti-Cancer Properties of W1469 (G2-8HQ) and W1469p (8HQ)
  • 8HQ and freshly synthesized G2-8HQ were prepared for in vitro anti-proliferative studies against the following cell lines with and without the presence of 10 ⁇ M Cu(+2): (1) A549: Breast cancer; (2) BT-549: epithelial cells from WE341W:216306:577531:1:ALEXANDRIA ductal tumor; (3) DU-145: human prostate cancer; (4) PANC-1: pancreatic cancer; (5) SU.86.86: a new adoptive pancreatic cell for immunotherapy studies; (6) RL: non- Hodgkin’s lymphoma; (7) LnCAP, Prostate cancer cell line; (8) A431, a squamous cell carcinoma line; and (9) UACC-62 a malignant melanoma cell line.
  • Item 1 Tube A (W1469) (500 uM when FBS added)
  • Item 2 Tube B (W1469g) (1000 uM when FBS added)
  • Item 3 Tube C (W1469)
  • Item 4 Tube D (W1469g)
  • Items 1 and 2 are sterile ready for the addition of 1ml of sterile FBS. Final concentrations after addition of 1ml: 500 ⁇ M for Tube A and 1000 ⁇ M for Tube B. Items 3 and 4 are described further below.
  • media containing 10% FBS and 20 ⁇ M CuCl2 are used in Tubes C and D only.
  • a and B are serially diluted in media with 10% FBS and no added copper.
  • the protocol method proceeds as follows: WE341W:216306:577531:1:ALEXANDRIA Seed 2, 96-well plates of A549 cells with 5,000 cells per well in a total volume of 50 ⁇ L per well. Leave overnight. See plate layout below for which wells to seed with 100 ⁇ L of media for media control. The following day, cells are exposed to compounds as described below.
  • Items 1 & 2 to make the 500 ⁇ M and 1000 ⁇ M Stocks of samples 1 and 2 (W1469 and W1469g): Add 1ml of sterile FBS to each Tube A and Tube B, swirl to mix. This results in Tube A at 500 ⁇ M stock and Tube B at 1000 ⁇ M.
  • Tube A (W1469), the following amounts are used: 500 ⁇ M: 10 mL as supplied 100 ⁇ M: 2 mL 500 ⁇ M Sample + 8 mL media 30 ⁇ M: 3 mL 100 ⁇ M Sample + 7 mL media 10 ⁇ M: 3 mL 30 ⁇ M Sample + 6 mL media 3 ⁇ M: 3 mL 10 ⁇ M Sample + 7 mL media 1 ⁇ M: 3 mL 3 ⁇ M Sample + 6 mL media 0.3 ⁇ M: 3 mL 1 ⁇ M Sample + 7 mL media 0.1 ⁇ M: 3 mL 0.3 ⁇ M Sample + 6 mL media
  • Tube B (W1469g)
  • Tubes C and D were as follows: 1000 ⁇ M: 10 mL as prepared above 300 ⁇ M: 3 mL 1000 ⁇ M Sample + 7 mL mix 100 ⁇ M: 3 mL 300 ⁇ M Sample + 6 mL mix 30 ⁇ M: 3 mL 100 ⁇ M Sample + 7 mL mix 10 ⁇ M: 3 mL 30 ⁇ M Sample + 6 mL mix 3 ⁇ M: 3 mL 10 ⁇ M Sample + 7 mL mix 1 ⁇ M: 3 mL 3 ⁇ M Sample + 6 mL mix 0.3 ⁇ M: 3 mL 1 ⁇ M Sample + 7 mL mix
  • 2 mM CuCl2 Dissolve 34 mg CuCl2 in 100 mL media (Filter Sterilize) 20 ⁇ M CuCl2 media: 2 m
  • Figure 2 is a graphic representation of the cytotoxicity of WT1469 (G2-8HQ) against A549 breast cancer cell line in the presence of Cu +2 ions.
  • Figure 2 there is a wide standard deviation at 1 and 0.5 ⁇ M indicating WE341W:216306:577531:1:ALEXANDRIA lack of bioavailable copper in the cell media for complete copper chelation and further illustrating that in some percentage of the screens all the cancer cells were killed at these concentrations.
  • Figure 3 reflects cytotoxicity of WT1469 (G2-8HQ) against the DU-145: human prostate cancer cell line, again in the presence of Cu +2 ions.
  • Figure 4 shows the cytotoxicity of WT1469 (G2-8HQ) against BT-549, namely epithelial cells from ductal tumor, in the presence of Cu +2 ions.
  • WT1469 G2-8HQ
  • BT-549 epithelial cells from ductal tumor
  • Figure 7 shows the results of cytotoxicity testing of WT1469 (G2-8HQ) against RL Cells (non-Hodgkin’s lymphoma) in the presence of Cu +2 ions. Again, in both cases, the testing showed that in a percentage of cases, all of the cancer cells were killed at concentrations between at 1 and 0.5 ⁇ M.
  • Three additional cell lines WE341W:216306:577531:1:ALEXANDRIA were also studied and described more completely in Example 9 provided herein. These cell lines included cytotoxicity testing of WT1469 (G2-8HQ) against LnCAP a prostate cancer, A431 a squamous carcinoma cell line and UACC-62 a malignant melanoma cell line.
  • Table 2 shows the IC50 ⁇ M determinations for G2-8HQ and 8HQ against the following cancer cell lines, both with and without the presence of 10 ⁇ M Cu in the cell media: (1) A549: Breast cancer; (2) BT-549: epithelial cells from ductal tumor; (3) DU-145: human prostate cancer; (4) PANC-1: pancreatic cancer; (5) SU.86.86: a new adoptive pancreatic cell for immunotherapy studies; (6) RL: non- Hodgkin’s lymphoma; (7) LnCAP: a prostate cancer cell line; (8) A431: a squamous cell carcinoma line; and (9) UACC-62: a malignant melanoma cell line.
  • Table 2 IC50 ⁇ M determinations for G2-8HQ and 8HQ against nine cancer cell lines IC50 [ ⁇ M] WE341W:216306:577531:1:ALEXANDRIA PANC-1 >500 ⁇ M >500 ⁇ M 18 ⁇ M 39 ⁇ M 9.3 ⁇ M 11.2 ⁇ M BT-549: Triple Negative Breast Cancer DU-145: Prostate Cancer PANC-1: Pancreatic Cancer Su.86.86 Pancreatic Cancer RL: Non Hodgkin’s Lymphoma LnCAP: Prostate Cancer A431: Squamous Cell Carcinoma UACC-62: Melanoma It should be noted with the exception of the most recent experiments A431 and UACC-62, the calculations of IC50s in Table 2 are based on the W1469 MW of the apo form (337 MW) and not the actual active copper complex (771 MW).
  • G2-8HQ is less stable in aqueous solutions at pH values lower than 8 or over time in organic solvents, it is often necessary to ensure proper conditions of pH in order to maximize G2-8HQ stability.
  • a pH of 5 has been shown to degrade the compound almost immediately, while dissolving in DMSO (without copper) yields over time the precipitated degradation product of the keto form of 2-8HQ (we determined by x-ray crystallography).
  • the G2-8HQ copper complex at pH values less than 8 results in rapid precipitated insoluble 2-8HQ copper complex by ejecting the glucuronic acid adduct to yield a copper complex of 2-8HQ (determined by x-ray crystallography under contract at John Hopkins University and shown in Figure 9 and described herein).
  • a green stable biologically active form of G2-8HQ was prepared as a copper complex using an excipient mixture inclusive of aqueous buffers at pH 8 – 8.2. The structure for this complex is shown in Figure 12.
  • 8HQ is sparingly soluble in water, but will generally be soluble in DMSO.
  • the 8HQ compound can rapidly form a copper complex in aqueous WE341W:216306:577531:1:ALEXANDRIA solutions to yield an aqueous insoluble bright yellow precipitate.
  • This precipitate when dissolved in DMSO, yields dark red prismatic crystals under slow evaporation.
  • the atomic structure of this complex was determined by x-ray crystallography under contract at John Hopkins and is shown in Figure 11. This structure may have important implications of the in vivo and in vitro activity of 8HQ, and its divalent copper structure may have superior ROS generation over other 8HQ analogs, whereas the crystallization from more aqueous alcohol solutions yields the classic structure which includes two water molecules (see Figure 10).
  • Figure 9A shows the G2-8HQ (W1469) copper complex in an excipient, with precipitation after 24 hours.
  • Figure 9B is an atomic structure determination by x-ray crystallography of dissolved and recrystallized (DMSO) G2-8HQ (W1469) precipitate.
  • DMSO dissolved and recrystallized
  • W1469p (8HQ) the complex of W1469p (8HQ) in aqueous solution is shown as confirmed by crystallography.
  • M Mn(II), Fe(II), Co(II), Cu(II), Ni(II), and Zn (II) for W1469p.
  • FIG. 12B shows the proposed copper complex of W1469 from aqueous synthesis based on determined copper complex structures of the 2,8HQ and 8HQ similarly produced.
  • Figure 13 a cursory examination was made of the anti-proliferative activity of G2-8HQ administered as a copper complex. It was noted in the anti-proliferative study that significant material was lost during sterile filtration of G2-8HQ evidencing that the biological activity of the complex was even significantly better than observed, and perhaps significantly so.
  • G2-8HQ provides a new anti-cancer, anti-viral, anti-bacterial, anti-parasitic, anti- neurodegenerative, anti-fungal agent with enhanced and highly desirable efficacy, safety, and clinical administrative characteristics.
  • G2-8HQ WE341W:216306:577531:1:ALEXANDRIA has unique desirable solubility and pro-drug like properties with the further expectation of enhanced safety profile and in the case of cancer applications, improved tumor partitioning.
  • G2-8HQ has a powerful anticancer activity against all cell lines tested and further shows superior biological activity when enhanced using copper chelation.
  • the testing as described herein was primarily done using copper chelation, but it would be understood that different metals could be substituted to achieve various desired activities against different cell lines and organisms, such metals include but are not limited to Cu, Zn, Fe, Co, Rh, Pt, etc.
  • metals include but are not limited to Cu, Zn, Fe, Co, Rh, Pt, etc.
  • other heavy metals such as arsenic, antimony, gold, vanadium in addition to platinum and iron have traditionally been used among cancer chemotherapy agents and thus could also be used in G2-8HQ complexes as set forth in this disclosure.
  • 8HQ and its derivatives has largely been attributed to their inherent chromophore heavy metal chelating properties, most notably Cu, Fe and Zn. In some cases the function is associated with the direct metal interference, such as in the inhibition of metalloprotease and for others the alteration in transition metal homeostasis or the creation of ROS (free radical, oxidative stress strongly implicated).
  • direct metal interference such as in the inhibition of metalloprotease and for others the alteration in transition metal homeostasis or the creation of ROS (free radical, oxidative stress strongly implicated).
  • ROS free radical, oxidative stress strongly implicated
  • the present inventors obtained a commercial sample of G8HQ and tested it in vitro under conditions with copper added and found a possible reading of >500uM IC 50, indicating no anti-proliferative activity, but such examination was cursory and not conclusive.
  • Oliveri 2012 designed an O-linked glucose adducts to the 8-hydroxy position of both 8HQ and CQ ( Figure 17).
  • the resulting pro-drug form as expected abrogated the copper binding and eliminated the anti-cancer activity.
  • the authors reasoned that the glucose adduct function as an inactive prodrug to be converted to the active 8HQ form by the hydrolysis of the glycosidic bond by beta- glucosidases in the cytoplasm of cancer cells.
  • the keto-enol chemistry of 2,8-dihydroxyquinoline (2-8HQ) (Fig. 21) is as follows: As and glucose or glucuronide derivatives, where the primary focus was on prodrug forms which release the aglycone drug form enzymatically by beta-glucosidase, the compounds of the present invention including G2-8HQ are active without beta-glucosidase Further, although not required in the case of G2-8HQ the reactive chemistry/instability of the glucuronide at position 2 yields a second pathway at acidic cytosolic pH, to release or WE341W:216306:577531:1:ALEXANDRIA “kick-off” the sugar moiety, which in principal should further enhance the antiproliferative effect is shown in Fig.22.
  • G2-8HQ can be administered with the glucuronic acid/glucose-based targeting intact. Furthermore, unlike hydrolyzed copper complexes of the activated drugs using Glu8HQ and G8HQ, G2-8HQ remains highly aqueous soluble.
  • EXAMPLE 8 Additional Advantages of G2-8HQ and its antiproliferative activity over the prior art
  • the anticancer activities of these compounds were first examined against A2780, A549, and MDA-MB-231 with and without copper and with and without glucose modification O-linked at the 8-hydroxy position. They reported unmodified 8HQ was about 9 to 27X higher in activity than the comparable tests with CQ. These trends were carried over in the glucose modifications, but with comparatively 10-fold lower activity, which further indicated the uncertainty with the results. Combined with the toxicity issue relating to the use of CQ, this uncertainty restricted efforts to move ahead with the use of such technology.
  • the cytotoxicity towards various cancer cell lines markedly increases ranging from a greater than 1000-fold increase with the RL – non-Hodgkin’s lymphoma, a greater than 90-fold increase for BT549, a greater than 68-fold increase for DU-145 prostate cancer, and a greater than 8-18 fold improvement with A459. These results are markedly superior to those reported by Oliveri 2011 even at higher copper concentrations (20 ⁇ M Cu +2 ).
  • the present inventors have shown that since anticancer and anti- microbial activities of 8HQ pharmacophores require copper to be effective, pre- complexation with copper would be highly desirable administrative form, and the ability to locate and use more suitable forms in this regard, such as G2-8HQ, is a huge advantage in the potential uses of these compounds for therapeutic purposes.
  • metal complexes cannot form if the glucose or glucuronide derivative is in place at the 8OH, and thus the prior art compounds synthesized and evaluated by Oliveri & Manson make pre-complexation impossible.
  • the copper complexes of 8-hydroxy quinolone and its congeners are highly insoluble in aqueous solutions which also makes them less desirable in this form.
  • G2-8HQ has: 1) superior solubility with or without complexed copper, and 2) superior and unique safety potential and biological activity that overcomes the previous issues with 8HQ as reflected in many previous studies.
  • G2-8HQ is administered in a form that does not complex it with copper ions in advance, and thus even when administered alone, G2-8HQ can be utilized effectively against cancer and other conditions as described in detail herein.
  • Table 5 A summary of additional comparative advantages of G2-8HQ over the art is shown below in Table 5.
  • Table 5 Comparative advantages and differences of G2-8HQ over prior art Compound Active Complexes Solubility of Cu Require Targets Parent Q WE341W:216306:577531:1:ALEXANDRIA GA8HQ No No None, (8HQ poor) Yes Yes 8HQ
  • several strategies for treatment and modes of delivery are possible in light of the showing herein regarding chemistry and safety profile of G2- 8HQ.
  • NMSC non-melanoma skin cancer
  • BCC basal cell carcinoma
  • SCC squamous cell carcinoma
  • Actinic keratosis is the most common pre-cancer; it affects more than 58 million Americans.
  • the current standard of care includes surgical excision (the most common method prescribed), cryogenics, topical treatments and radiation treatments.
  • Photodynamic Therapy Aminolaevulinic acid (Levulan)* Side Effects: Burning, Itching or Tingling, Rash or redness Light sensitivity (bright lights/sunshine)
  • Topical Chemotherapy Fluorouracil 4 to 12 wks Side Effects: Burning or itching, rash or redness, sore or tender skin, serious allergic reaction to drug (rare)
  • Immune response modifier Zyclara, Alara (Imiquimod) up to 8 wks Side Effects: Redness, bleeding or flaking skin, swelling, blistering, sting or pain.
  • Basil Cell Carcinoma Rationale Basil Cell Carcinoma is the most common form of skin cancer with 3.6 Million cases diagnosed each year and rising. It is estimated that 80% of all newly diagnosed skin cancers are BCC. Although rarely fatal, it can be painful and disfiguring and, in some cases, become dangerously invasive. The most common forms of treatment include surgery, radiation treatment, immunotherapy, systemic and topical chemotherapy, and other variations including laser therapy. The currently approved topical treatments for BCC are usually only recommended for more superficial tumors and more extensive monitoring is required because they are generally not effective in destroying cancer cell deeper below the surface. A more complete description of treatment options and their relative effectiveness has been described by the American Cancer Society.
  • W1469 is a novel small molecule anti-cancer drug candidate which contains a tumor targeting functional group and has been shown effective against a variety of cancers in vitro. (most recently including squamous cell carcinoma)
  • Drug Vehicle Topical gel containing 0.5mg/ml W1469 in proprietary aqueous alcohol gel, applied initially once daily using a suitable topical applicator.
  • Treatment/Patient protocol used for the patient testing was as follows: 1. Photograph the application site prior to starting the protocol. Note any changes in lesion size, color, etc. of treatment area. 2. Remove a loaded syringe from the freezer, dry ice or refrigerator and allow to gradually warm to room temperature. 3. Photograph the syringe each time prior to application. Note the color of the gel contained in the syringe. 4. Lightly clean the skin surface with alcohol wipe. 5.
  • FIG.23 A photo of the individual before treatment is included in Fig.23. Patient condition was monitored and photographed regularly during the treatment period. Treatment was given throughout a three week period including certain days where treatment was applied at a higher concentration): As shown in Fig.24, at the end of the treatment period, the treatment achieved significant amelioration of the patient’s condition and did not result in scarring or other disfigurement as is often the case with other treatments.
  • WE341W:216306:577531:1:ALEXANDRIA Single Patient Clinical Study Design: Individual 2 Self-administered, variable treatment protocol, drug concentrations and vehicle carrier.
  • another lesion returned to the patient’s right cheek displaying same pattern consistent with basal cell carcinoma. Therapy was reintroduced on a three times-daily dosing schedule and with ethanol-based carrier molecule.
  • Lesion displays centralized necrotic tissue and hyperkeratosis. After two days of treatment the centralized necrotic core came out of the lesion resulting in a bloody clot. The centralized portion of the lesion slowly healed over the next 5-day period. Continued healing of the centralized portion of the lesion during the 5-day period status post central necrotic tissue extrusion was shown. During this period the lesion began to flatten, the area became pain free, and localized tissue became less erythematic. A bloody clot in central area resolved and crater size decreased. No evidence of centralized necrosis noted and lesion size markedly decreased. Lack of pain and marked reduction in lesion hyperkeratosis was noted as well.
  • SAFETY/TOXICITY • Treatment and application is not painful* • Doesn’t inflame or injure adjacent tissue • No side effects were noted Applications with DMSO as the carrier were briefly painful following administration and discontinued. This was later determined to be the drug carrier and not the drug. Ethanol-based carriers exhibit mild stinging sensation upon application.
  • the compounds of the present disclosure can be used effectively and with fewer side effects in methods of treating cancer and other conditions such as microbial and viral infections, and thus have potential use as promising therapeutics for a broad range of disease indications as described herein.
  • a clioquinol-containing Pluronic®F127 polymeric micelle system is effective in the treatment of visceral leishmaniasis in a murine model.

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Abstract

Conformément à la divulgation, sont proposés du 2,8-dihydroxyquinoléine-bêta-D-glucuronide et d'autres composés apparentés destinés à être utilisés dans des méthodes de traitement du cancer et d'autres affections, telles que des méthodes antivirales et antimicrobiennes. Un tel composé est le produit de dégradation métabolique intermédiaire acide 8-hydroxy-2-quinolinyle bêta-D-glucopyranosiduronique (ou G2-8 HQ). Le composé G2-8 HQ et d'autres composés similaires sont utilisés dans des compositions et des méthodes pour le traitement du cancer et d'autres pathologies comprenant des applications antivirales, antimicrobiennes et d'autres applications thérapeutiques. Sont proposés d'autres composés d'hydroxyquinoléine destinés à être utilisés dans le traitement du cancer et d'autres pathologies, y compris du 2,8-quinoléinediol (2-8 HQ), et d'autres composés comprenant ces dérivés de glucose ou de glucides au niveau de l'hydroxyquinoléine substituée aux positions 3-7 du cycle d'hydroxyquinoléine. Ces composés peuvent être utilisés individuellement ou en combinaison avec d'autres fractions comprenant d'autres hydroxyquinoléines et des acides gras oméga, et l'efficacité thérapeutique de ces composés peut être amplifiée en présence d'un métal chélatant tel que le cuivre ou d'autres chélates métalliques.
PCT/US2024/032216 2023-06-02 2024-06-03 Dérivés de 2,8-dihydroxyquinoléine glucuronide présentant des propriétés améliorées destinés à être utilisés en tant qu'applications anticancéreuses, antivirales, antimicrobiennes et autres applications thérapeutiques Pending WO2024249983A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190167765A1 (en) * 2009-04-24 2019-06-06 Albumin Therapeutics Human serum albumin-based topical ointment for treatment of acne, psoriasis, egfr-induced toxicity, premature skin aging and other skin conditions
US20200123172A1 (en) * 2015-07-06 2020-04-23 Gilead Sciences, Inc. Cot modulators and methods of use thereof
WO2021178420A1 (fr) * 2020-03-03 2021-09-10 Twentyeight-Seven, Inc. Composés ciblant des protéines de liaison à l'arn ou des protéines modifiant l'arn
US20220023324A1 (en) * 2018-12-20 2022-01-27 Abivax Quinoline derivatives for use in the treatment of inflammation diseases
US20230041518A1 (en) * 2018-10-30 2023-02-09 Gilead Sciences, Inc. Quinoline derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190167765A1 (en) * 2009-04-24 2019-06-06 Albumin Therapeutics Human serum albumin-based topical ointment for treatment of acne, psoriasis, egfr-induced toxicity, premature skin aging and other skin conditions
US20200123172A1 (en) * 2015-07-06 2020-04-23 Gilead Sciences, Inc. Cot modulators and methods of use thereof
US20230041518A1 (en) * 2018-10-30 2023-02-09 Gilead Sciences, Inc. Quinoline derivatives
US20220023324A1 (en) * 2018-12-20 2022-01-27 Abivax Quinoline derivatives for use in the treatment of inflammation diseases
WO2021178420A1 (fr) * 2020-03-03 2021-09-10 Twentyeight-Seven, Inc. Composés ciblant des protéines de liaison à l'arn ou des protéines modifiant l'arn

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