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WO1995009630A1 - Composes a action antiproliferative dirigee contre des cellules - Google Patents

Composes a action antiproliferative dirigee contre des cellules Download PDF

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Publication number
WO1995009630A1
WO1995009630A1 PCT/US1994/011230 US9411230W WO9509630A1 WO 1995009630 A1 WO1995009630 A1 WO 1995009630A1 US 9411230 W US9411230 W US 9411230W WO 9509630 A1 WO9509630 A1 WO 9509630A1
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Prior art keywords
curacin
cells
amount
stereoisomers
formulation
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Ceased
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PCT/US1994/011230
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English (en)
Inventor
William H. Gerwick
Philip J. Proteau
Dale G. Nagle
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Oregon State University
Oregon State
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Oregon State University
Oregon State
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Priority claimed from US08/134,282 external-priority patent/US5324739A/en
Application filed by Oregon State University, Oregon State filed Critical Oregon State University
Priority to AU79648/94A priority Critical patent/AU7964894A/en
Publication of WO1995009630A1 publication Critical patent/WO1995009630A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to chemical compounds, isolated and purified from a marine blue-green alga (cyanobacterium), exhibiting biological activity.
  • Curacin B Another isomer, termed “Curacin B”, has the following chemical structure:
  • Curacin C Yet another isomer, termed “Curacin C”, has the following chemical structure:
  • Curacin D Another isomer, formed by chemically altering Curacin A, is termed “Curacin D” and has the following chemical structure:
  • Curacin A A variant of Curacin A, termed “15,16-dihydrocuracin A,” has the following chemical structure:
  • R is an alkyl group having eight to twenty-two carbons, and can include double carbon-carbon bonds and/or other lipophilic groups
  • R' is an alkyl group having one to six carbon atoms, and can include rings or carbon-carbon double bonds.
  • FIG. 1 is a schematic depiction of the general protocol used to purify Curacin A and Curacin B.
  • FIG. 2 is a plot of the cytotoxicity of thin-layer- chromatography fractions obtained during purification of these isomers, as determined using a brine shrimp assay.
  • FIG. 3 is a ⁇ -NMR spectrum of a biologically active fraction obtained by vacuum chromatography of an extract from Lvn ⁇ bva maiuscula. showing a shouldered triplet indicating that the fraction is a mixture of at least two isomers, Curacins A and B.
  • FIG. 4 is a ⁇ -NMR spectrum of the fraction of FIG. 3 after purification via HPLC so as to separate the isomers.
  • FIG. 5 is a plot of data obtained from a brine shrimp assay performed with the unpurified extract from Lvn ⁇ bva maiuscula.
  • FIGS. 6A-6I are dose-response curves showing the effect of the unpurified extract on various cancer cell lines in culture, as set forth in Examples 2-61.
  • FIG. 7 shows mean-plots of data from FIGS. 6A-6I, wherein the left-hand mean plot is of GI ⁇ , data, the middle mean plot is of TGI data, and the right-hand mean plot is of LC M data.
  • FIGS. 8A-8I are dose-response curves showing the effect of purified Curacin A on various cancer cell lines in culture, as set forth in Examples 62-121.
  • FIG. 9 shows mean-plots of data from FIGS. 8A-8I, arranged similarly to the plots shown in FIG. 7.
  • FIGS. 10A-10I are further dose-response curves showing the effect of purified Curacin A on various cancer cell lines in culture, as set forth in Examples 122-181.
  • FIG. 11 shows mean-plots of data from FIGS. 10A-10I, arranged similarly to the plots shown in FIG. 7.
  • FIGS 12A-12C are dose-response curves showing the effect of a purified mixture of Curacin B and Curacin C (95:5) on various cancer cell lines in culture, as set forth in Examples 182-241.
  • FIG. 13 shows mean-plots of data from FIGS. 12A-12C, arranged similarly to the plots shown in FIG. 7.
  • FIGS. 14A-14C are dose-response curves showing the effect of 15,16-dihydrocuracin A on various cancer cell lines in culture, as set forth in Examples 242-301.
  • FIG. 15 shows mean-plots of data from FIGS. 14A-14C, arranged similarly to the plots shown in FIG. 7.
  • FIGS. 16A-16B are dose-response curves showing the effect of Curacin D on various cancer cell lines in culture, as set forth in Examples 302-361.
  • FIG. 17 shows mean-plots of data from FIGS. 16A-16B, arranged similarly to the plots shown in FIG. 7.
  • the alga harvested at a depth of 0.3 m, was preserved in 90- percent isopropyl alcohol and transported to the U.S. In the laboratory, the alga was subjected to two chloroform-methanol extractions to isolate lipophilic compounds and an aqueous methanol extraction to isolate hydrophilic compounds. Each chloroform- methanol extraction was performed by washing algal tissue in 2:1 chloroform:methanol and collecting the supernatant liquid. The aqueous methanol extraction was performed by washing algal tissue in a 75 % solution of methanol in water and collecting the supernatant liquid. The chloroform-methanol extract exhibited substantial toxicity in a brine-shrimp assay, with an LD 50 of about 25 ng/mL. (Further details on the brine-shrimp assay are set forth below in Example 1.) The brine-shrimp assay was used as needed to evaluate the results of procedures used to purify the compound.
  • the alga was extracted using chloroform-methanol, yielding 2.39 g of "crude" extract.
  • a portion, 543 mg, of the crude extract was subjected to two separate stages of vacuum chromatography as shown in FIG. 1.
  • the extract was eluted using increasingly greater concentrations (5-100 % in 5-percent increments) of ethyl acetate in hexane.
  • ten fractions of the eluate were collected. Each fraction was tested for cytotoxicity on cultured MRC-5 cells that were actively dividing, cultured MRC-5 cells that were confluent (and thus not dividing), and actively dividing Chinese hamster AB1 tumor cells.
  • the second fraction collected in the first stage representing elution from 5 to 10 % ethyl acetate, had a mass of 314 mg and exhibited the greatest cytotoxicity.
  • the second stage of vacuum chromatography was performed on the second fraction collected in the first stage. Elution in the second stage was performed within a much smaller range of increasingly greater amounts of ethyl acetate in hexane (1 to 5 % in 0.5 to 1.0 % increments). The first four fractions were inactive, but fractions 5-9 showed substantial activity. Fractions 5-9 were pooled and, as such, represented about 200 mg total. The pooled fractions 5-9 were apparently contaminated by several fatty acids as determined by the following procedures.
  • the mixture was methylated using diazomethane (CH-_iJ 2 ) ⁇ to which the Curacin A and Curacin B compounds were found to be unreactive (as further confirmed by ⁇ -NMR) .
  • GC-MS gas chromatography-mass spectrometry analysis of the methylated mixture revealed that the active compound was present as a mixture with the methylated fatty acids methyl hexadecanoate, methyl-9-octadecenoate, and methyl 11- hexadecenoate, in about equal amounts.
  • MTT 3-[4,5-dimethylthiazol-2-yl]- 2,5-diphenyl tetrazolium bromide
  • PBS phosphate-buffered saline
  • MRC-5 Human embryonic lung cells were obtained from the American Type Culture Collection. The cells were grown in Eagle's Minimum Essential Medium with Earle's salts (EMEM, JRH Bioscience) supplemented with 10% fetal calf serum (Hyclone), 0.75 mg/mL NaHC0 3 , 100 units of penicillin per mL, and 100 ⁇ g streptomycin per mL (Gibco Labs).
  • cell growth and survival was determined calorimetrically, based upon the uptake and reduction of the tetrazolium salt, MTT, to a blue-colored formazan product by mitochondrial enzymes of living cells.
  • the effect of the fractions, as potential inhibitors at different stages of the cell cycle, was determined by performing the assay using both resting and rapidly dividing cells. Plates exhibiting either confluent cells (resting phase) or proliferating cells (rapidly dividing phase) were incubated with various concentrations of the extracts for four days at 37°C in air containing 5% C0 2 .
  • the medium was aspirated, the cells were rinsed once using PBS, and 1.0 mg/mL of MTT was added to each well.
  • the plates were incubated with MTT for three hours, after which the MTT was aspirated and isopropanol was added to dissolve any formazen crystals that formed. Plates were "read" on an Elisa reader at 570 nm (principal wavelength) and again at 650 wavelength (reference wavelength) to correct for non-specific background absorbance, using a Thermomax
  • Curacin A having the empirical formula possessed seven degrees of unsaturation, five of which were due to double bonds and two due to rings.
  • Curacin A was determined to have the structural formula as shown below:
  • Curacin B isomer present in the minor fraction is a stereoisomer of Curacin A, and has the structural formula as shown below:
  • Curacin A is trans at the C7-C8 and C9-C10 positions
  • Curacin B is cis at these positions.
  • Data from ⁇ -'H COSY (correlation spectroscopy) and ⁇ - l3 C-HETCOR (heteronuclear chemical shift correlation) were used to ascertain the structure for the left-hand portion of Curacin A.
  • the left-hand portion began with a monosubstituted terminal olefin that was adjacent to a methylene group. Neighboring the methylene group was a deshielded methine (C13) that was shown by HMBC (heteronuclear multiple bond correlation) to bear an O-methyl group.
  • C13 deshielded methine
  • Sequential ⁇ - ⁇ correlations placed two consecutive methylene groups (Cll and C12) contiguous to the deshielded methine, the latter methylene group being adjacent to a quaternary carbon.
  • the middle portion of the Curacin A molecule was found to begin with a terminal methylene group (Cl) bearing a heteroatom (the sulfur in the 5-membered ring) adjacent to a methine carbon (C2) also bearing a heteroatom (the nitrogen in the 5-membered ring) .
  • the proton adjacent to the nitrogen atom was coupled to an olefinic proton at 65.69, which in turn coupled by 10.7 Hertz to its olefinic partner.
  • C5 and C6 Two methylene groups (C5 and C6) spanned between this olefin (C3 and C4) and a conjugated diene (C7-C10).
  • the first of the olefins (C7 and C8) in the conjugated diene was disubstituted and trans while the second olefin (C9 and CIO) was trisubstituted and possessed methyl (C17) and alkyl (C11-C16) substituents at its distal portion (CIO).
  • the geometry of the second olefin was shown to be £ by the high-field 13 C-NMR chemical shift of the methyl group (C17) at 516.56.
  • the structure on the right-hand portion of the molecule was readily formulated, from spin-coupling information, as a cis- disubstituted cyclopropyl ring with methyl and quaternary carbon substituents.
  • HMBC was used to make further confirmation of structure.
  • the protons alpha to the two heteroatoms in the five-membered ring were both correlated to the quaternary carbon (C18).
  • C18 quaternary carbon
  • long-range coupling was observed between the olefinic proton at 56.02 (on C9) and the methylene carbon at 535.77 (Cll).
  • Assigning sulfur as the heteroatom bonded to Cl and nitrogen as the heteroatom bonded to C2 were based on comparisons of 13 C-NMR chemical shifts with model compounds, Hawkins et al., J. Med. Chem. 33:1634-1638 (1990); and Jalal et al., J. Am. Chem. Soc. 111:292-296 (1989), thereby defining a thiazoline ring.
  • Curacin A was found to be a substantially planar molecule having a cyclopropyl ring and long-chain alkene substituents.
  • Curacin A appears to be different from any other known chemical.
  • the alkylated thiazoline portion of the molecule is also believed to be unique, but appears to have some similarity to the potent cytotoxin ⁇ patellazole A-C from the tunicate Liss ⁇ clinum patella. Zabriskie et al., J. Am. Chem. Soc. 110:7919 (1988). I.e., the patallazoles possess four-carbon epoxides and long polyketide chain substituents on a thiazole ring.
  • patellazoles and Curacin A both have similar chromophores at about the same location relative to the thiazoline/thiazole rings. Similar substituted diene or triene functionalities are observed in two other well-known an imi otic agents, maytansine and rhizoxin.
  • Curacin A is formed by the union of two polyketides, joined via a decarboxylated cysteine residue. Based upon comparisons with analogous biologically active portions of other compounds that exhibit biological activity, the biologically active portions of Curacin A are believed to include the heterocyclic ring, and the cis C3-C4 group. In any event, Curacins A and B appear to readily penetrate cell membranes, probably due to the substantial lipophilicity of these compounds (particularly the long olefinic "tail" extending away from the heterocyclic ring) .
  • Curacins A, B, C, and D have been found to be cytotoxic compounds that appear to be antimitotics, probably by interfering with cellular mechanisms of tubulin formation. Tests performed using nearly sixty different cancer cell lines (see Examples below) indicate that the cytotoxic profiles of Curacin A and its isomers and variants share certain similarities with other antimitotic agents, such as the Vinca alkaloids and taxol, that are useful as antineoplastics.
  • Curacin A and/or an isomer or variant thereof
  • a pharmaceutically inert carrier suitable for administration to an animal subject, in a manner. similar to that used for preparing such formulations of conventional antimitotic compounds.
  • Curacins A and B for reducing a population of representative arthropods (brine shrimp; see Example 1) indicate that Curacin A and its isomers and variants have general utility as agents for reducing populations of arthropods such as insects.
  • Curacin A and isomers and variants thereof, have substantial antiproliferative activity against living cells in culture.
  • Curacin A and its isomers and variants would be expected to also exhibit herbicidal properties. Preliminary experiments indicate that these compounds at least exhibit anti- fungal activity.
  • Curacin B The fraction that contained Curacin B was also found to contain yet another compound related to Curacins A and B. This new compound, named "Curacin C”, was determined to have the following structure:
  • Curacin C is a stereoisomer of Curacin A, wherein Curacin C is cis at the C9-C10 positions.
  • Curacins A, B, and C can be converted from one to another by heating under conditions in which the compounds are not thermally degraded. 4. Curacin D and 15.16-Dihvdrocuracin A
  • Curacin D Semi-synthetic analogs of Curacin A were prepared. One such analog, termed "Curacin D”, was found to have the following structure:
  • Curacin D exhibits a cis conformation at the cyclopropyl ring whereas Curacin A exhibits a trans conformation at the cyclopropyl ring
  • Curacin D is a stereoisomer of Curacin A.
  • Curacin D has been evaluated for colchicine binding and, in such regard, is at least as potent as Curacin A.
  • this compound has a single bond between C15 and C16 instead of a double bond as found in Curacin A.
  • R is any medium to long alkyl chain (i.e., 8 to 22 carbons), with or without carbon-carbon double bonds or other lipophilic groups; and R' is any short alkyl chain (i.e., 1 to 6 carbons) with or without rings or carbon-carbon double bonds.
  • R is any medium to long alkyl chain (i.e., 8 to 22 carbons), with or without carbon-carbon double bonds or other lipophilic groups; and R' is any short alkyl chain (i.e., 1 to 6 carbons) with or without rings or carbon-carbon double bonds.
  • the residue was dissolved with a suitable volume of ethanol to yield a concentration of 0.1 mg residue per ⁇ L ethanol.
  • Four vials were prepared, the first containing 50 ⁇ L of the ethanol solution, the second containing 10 ⁇ L of the ethanol solution plus 40 ⁇ L ethanol, the third containing 2.5 ⁇ L of the ethanol solution plus 47.5 ⁇ L ethanol, and the fourth containing none of the solution and 50 ⁇ L ethanol (serving as a negative control). Between 10 and 15 live brine shrimp were placed in each vial and stored for 24 hours, after which the number of live and dead shrimp were tallied for each vial.
  • the number of dead shrimp was divided by the total number of shrimp added to the vial, and multiplied by 100 to yield the percent mortality for each vial.
  • the data are plotted as percent alive versus the log 10 of the concentration of extract added to the corresponding vials.
  • the LC M concentration value is the concentration of the extract at which 50% of the brine shrimp are killed. Examples 2-61
  • an extract of Lvnqbva maiuscula containing Curacins A and B was subjected to the drug screening procedure employed by the National Cancer Institute for the screening of drugs having possible anticancer utility.
  • the screening procedure employed a diverse, disease-oriented panel consisting of 60 different human tumor cell lines organized into seven disease-specific subpanels.
  • the extract was tested over a wide range of concentrations for cytotoxic or growth-inhibitory effects against each cell line comprising the panel.
  • the seven subpanel ⁇ represented diverse histologies (leukemias, melanomas, and tumors of the lung, colon, kidney, ovary, and brain).
  • the extract was tested over two days in which the cells were continuously exposed to five log 10 -spaced concentrations of-the drug starting at 10"* ⁇ g/mL.
  • the tests produced 60 individual dose- response curves, one for each cell line (i.e., one for each example) .
  • FIGS. 6A-6I The data are disclosed in FIGS. 6A-6I as dose-response curves.
  • the data of FIGS. 6A-6I are summarized using a mean-graph format, as shown in FIG. 7.
  • a concentration of the extract that produced a target level response was calculated for each cell line.
  • Three different response parameters were evaluated.
  • the first response parameter was the "GI M ,” which is the concentration of the extract that produced an apparent 50% decrease in the number of tumor cells relative to the appropriate control (not exposed to extract) at the end of the incubation period.
  • the second response parameter was the "TGI,” which is the concentration at which the number of tumor cells remaining at the end of the incubation period substantially equaled the number of tumor cells existing at the start of the incubation period.
  • the third response parameter was the "LC ⁇ ,” which is the concentration of extract that caused an apparent 50 percent reduction in the number of tumor cells relative to the appropriate control (not exposed to extract) at the start of the incubation period.
  • mean graph e.g., left graph of FIG. 7
  • the relative position of the vertical reference line along the horizontal concentration axis is obtained by averaging the negative logioGIjo values for all the cell lines tested against the extract.
  • Horizontal bars are then plotted for the individual negative log 10 GI ⁇ values of each cell line relative to the vertical reference line.
  • the GI M graph thus provides a characteristic fingerprint for the extract, displaying the individual cell lines that are proportionately more sensitive than average (bars extending to the right of the reference line) or proportionately less sensitive than average (bars extending to the left of the reference line).
  • the length of a bar is proportional to the difference between the log l0 GIj ⁇ value obtained with the particular cell line and the mean (represented by the vertical reference line). For example, for a given cell line, a bar extending three log units to the right of the mean reflects an individual cellular sensitivity 10 3 times greater than the mean of all the cellular responses to the extract.
  • COMPARE A computer program called COMPARE is used by the National Cancer Institute to explore similarities and differences in the mean graph fingerprint of the sample drug compared to mean graph fingerprints of compounds in the standard agent database. COMPARE is used to rank the similarity of the mean graph profile of the sample extract or drug to the patterns of all the other compounds in the NCI screening database or a defined subset thereof.
  • 15-16-dehydrocuracin A was tested according to a 60 cell-line assay as described above in Examples 2-61. Dose- response data are shown in FIGS. 14A-14C, and mean-plot data are shown in FIG. 15. Examples 302-361:
  • Curacin D was tested according to a 60 cell- line assay as described above in Examples 2-61. Dose-response data are shown in FIGS. 16A-16C, and mean-plot data are shown in FIG. 17.

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Abstract

Composés cytotoxiques isolés et purifiés à partir d'une cyanobactérie marine Lyngbya majuscula. Ces composés spécifiques sont appelés 'Curacine A', 'Curacine B' et 'Curacine C', des isomères semi-synthétiques et variantes étant appelés 'Curacine D' et '15,16-dihydrocuracine A'. Lesdits composés présentent une activité biologique importante contre les cellules prolifératives et se révèlent antimitotiques. Des procédés d'utilisation desdits composés sont également décrits. Les parties actives de ces molécules comprennent au moins le cycle thiazoline et deux groupes alkyle attachés à des parties séparées du cycle, y compris un groupe alkyle C1-C6 court, avec ou sans cycles ou liaisons doubles, et un groupe alkyle C8-C22 long, avec ou sans liaisons doubles ou autres fractions lipophiles.
PCT/US1994/011230 1993-10-07 1994-10-03 Composes a action antiproliferative dirigee contre des cellules Ceased WO1995009630A1 (fr)

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US08/134,282 US5324739A (en) 1993-10-07 1993-10-07 Compound exhibiting antiproliferative activity against cells
US134,282 1993-10-07
US24386894A 1994-05-16 1994-05-16
US243,868 1994-05-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006267A3 (fr) * 2000-07-19 2003-01-30 Univ Pittsburgh Synthese et evaluation biologique d'analogues de la curacine a, produit naturel marin a activite antimitotique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON, Volume 43, No. 8, issued 1987, P. JUTTEN et al., "Syntheses of the Methyl Glycosides of Curacin, A-B Fragment Found in Avilamycin-A and -C, Curamycin-A, Flambamycin and Everninomicin-2 and of its Artificial Regioisomer Isocuracin", pages 4133-4140. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006267A3 (fr) * 2000-07-19 2003-01-30 Univ Pittsburgh Synthese et evaluation biologique d'analogues de la curacine a, produit naturel marin a activite antimitotique

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