WO2002027010A1 - Compose a base de xanthone - Google Patents
Compose a base de xanthone Download PDFInfo
- Publication number
- WO2002027010A1 WO2002027010A1 PCT/JP2001/008566 JP0108566W WO0227010A1 WO 2002027010 A1 WO2002027010 A1 WO 2002027010A1 JP 0108566 W JP0108566 W JP 0108566W WO 0227010 A1 WO0227010 A1 WO 0227010A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- cells
- wss2138
- culture
- chloroform
- Prior art date
Links
- JNELGWHKGNBSMD-UHFFFAOYSA-N xanthone powder Natural products C1=CC=C2C(=O)C3=CC=CC=C3OC2=C1 JNELGWHKGNBSMD-UHFFFAOYSA-N 0.000 title claims abstract description 8
- -1 Xanthone compound Chemical class 0.000 title claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 150000007964 xanthones Chemical class 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229910001923 silver oxide Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 235000019733 Fish meal Nutrition 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002518 antifoaming agent Substances 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000004467 fishmeal Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011218 seed culture Methods 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 230000028070 sporulation Effects 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- VFYFMNCKPJDAPV-UHFFFAOYSA-N 2,2'-(5-oxo-1,3-dioxolan-4,4-diyl)diessigs Chemical compound C1N(C2)CN3CN1CN2C3.OC(=O)CC1(CC(O)=O)OCOC1=O VFYFMNCKPJDAPV-UHFFFAOYSA-N 0.000 description 1
- HYPYXGZDOYTYDR-HAJWAVTHSA-N 2-methyl-3-[(2e,6e,10e,14e)-3,7,11,15,19-pentamethylicosa-2,6,10,14,18-pentaenyl]naphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 HYPYXGZDOYTYDR-HAJWAVTHSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- RFSUNEUAIZKAJO-VRPWFDPXSA-N D-Fructose Natural products OC[C@H]1OC(O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-VRPWFDPXSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- XKGZSMVZKNMJBZ-UHFFFAOYSA-N Lysolipin X Natural products COC1C(O)c2cc3C(OC)C4OCOC5=C6Oc7c(OC)c(Cl)ccc7C(=O)C6=C(O)C(O)(C45)c3c(O)c2C(=O)N1C XKGZSMVZKNMJBZ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- PNNNRSAQSRJVSB-BXKVDMCESA-N aldehydo-L-rhamnose Chemical compound C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-BXKVDMCESA-N 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 239000012141 concentrate Substances 0.000 description 1
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- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
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- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 1
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- 208000025113 myeloid leukemia Diseases 0.000 description 1
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- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 239000000049 pigment Substances 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
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- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
Definitions
- the present invention relates to a novel xanthone compound having an antitumor effect.
- An object of the present invention is to provide a novel xanthone compound having an antitumor effect. Disclosure of the invention
- the present inventors have isolated a large number of strains from soil and plants, and conducted various studies on metabolites of the strains.As a result, the present inventors have found that certain strains produce novel xanthones having strong antitumor activity. I found it. Furthermore, the present inventors have chemically modified this novel substance, found a derivative thereof that has maintained a strong antitumor effect, and have completed the present invention.
- the present invention provides a compound represented by the formula (I):
- R 1 and R 2 are each a hydrogen or a methyl group, and ⁇ is a compound represented by the following formula ( ⁇ ) or formula (IV)
- the strain producing the compound of the formula (I) (hereinafter referred to as WSS2138) is a strain newly isolated from the natural world by the present inventors, and the name of the microorganism is rstreptomyces sp. National Institute of Advanced Industrial Science and Technology Patent Organism Depositary Center (IP0D)
- the underlying hyphae are well-developed and irregularly branched, but no division is observed.
- Sporulation The aerial hyphae are poorly formed, and the spore chain is usually a loop with a tip of 1-3 turns or a dense spiral (10-20 spores).
- the spores are 0.6 to 0.7 urn in width, Si 0 to 0.5 m in length, cylindrical in shape, and smooth in surface. No sporulation is observed in the agar medium. Neither the formation of sporangia sclerotium nor the spore motility is observed.
- B. Cultural properties
- Table 1 shows the results of macroscopic observations when the cells were cultured at 28 ° C for 14 days on various media.
- the c-color display refers to the system color name of the Japan Standards Association, JIS Color Name Book (1985).
- Production of WSS2138 is carried out by culturing TA-0410 in a medium containing various nutrients under aerobic conditions in accordance with the production of general fermentation products.
- the medium is mainly a liquid medium and consists of a carbon source, a nitrogen source, and inorganic salts. If necessary, vitamins, precursors and antifoaming agents can be added, and the pH is adjusted to around 7.
- a carbon source for example, glucose, sucrose, dextrin, glycerin, starch or the like is used alone or in combination.
- the nitrogen source for example, meat excise, oatmeal, yeast extract, soy flour, polypeptone, corn steve liquor, urea, ammonium salt, etc. are used alone or in combination.
- an inorganic salt For example, monopotassium phosphate, magnesium sulfate, sodium chloride, calcium carbonate, or the like is used alone or in combination.
- Adekinol or a silicon compound can be used.
- Aerobic culture such as shaking culture and aeration and stirring culture is suitable for the culture method, and the pH is 4 to 10 and 25 to 35. Incubate at C for 2-5 days, preferably at pH 6-8, 25-28 for 4 days.
- the WSS2138 produced by this culture can be isolated according to a general method for collecting fermentation products.
- the following method is effective. That is, after completion of the culture, a culture filtrate is obtained by centrifugation or filtration, adsorbed on a polystyrene resin such as Diaion HP-20 (trade name, manufactured by Mitsubishi Chemical Corporation), and then an organic solvent such as a lower alcohol or acetone. To elute. The cells are extracted with an organic solvent such as lower alcohol or acetone.
- the bacterial cell extract and the eluate from the adsorption resin are combined and concentrated under reduced pressure to remove the organic solvent, and then transferred to a non-water-soluble organic solvent such as ethyl acetate, black form, and n-butanol. This is concentrated to a syrup.
- This sample is dissolved again in an organic solvent such as benzene, ethyl acetate, acetone, methanol, or chloroform, and then silica gel column chromatography, gel filtration column chromatography, and column chromatography packed with ODS for reverse layer partitioning.
- the compound of the present invention can be purified and isolated by subjecting it to high performance liquid chromatography.
- the structure of the WSS2138 obtained by the above purification method was determined by the analysis of the molecular weight, ultraviolet absorption spectrum, —NMR spectrum, 13 C—NMR spectrum, and the like, as in the formula (I).
- Figure 1 shows the results measured by the KBr method.
- Figure 2 shows the measurement results in deuterated dimethyl sulfoxide at 500 MHz.
- Figure 3 shows the results of measurement at 125 MHz in deuterated dimethyl sulfoxide.
- the methylated WSS2138 can be produced by reacting WSS2138 with a methylating agent in the presence of a base.
- a methylating agent methyl iodide, dimethyl sulfate, methyl methanesulfonate, and the like are used as the methylating agent, and lithium hydroxide, sodium hydrogen carbonate, potassium carbonate, silver oxide, triethylamine, and the like are used as the base.
- a reaction solvent an organic solvent which does not adversely influence the reaction, for example, N, N-dimethylformamide, dimethyl sulfoxide, getyl ether, tetrahydrofuran, chloroform, and acetonitrile is used.
- the reaction temperature is usually from about 170 ° C. to 150 ° C., preferably from 130 to 80 ° C.
- the reaction time is Incubate for 10 minutes to 10 hours.
- a liquid culture medium containing 2.5% soluble starch, 1% glucose, 0.5% fishmeal, 0.5% pharma media, 0.3% NZ case, 0.2% yeast extract and 0.2% calcium carbonate is placed in a 300m1 Erlenmeyer flask and placed at 120 ° C, sterilized at 2 atmospheres for 20 minutes.
- the TA-0410 strain was inoculated into this sterile medium, and the cells were subjected to rotary shaking culture at 200 rpm for 3 days at 28 to obtain seed culture.
- a sterile liquid medium consisting of 2% oatmeal, 1% glucose, 2.5% dextrin, 1% pharma media, 0.5% fishmeal, 0.5% molasses, 0.2% ebios, and 0.3% calcium carbonate was added to a 500ml triangle.
- the flask was placed in a flask, and 100 ml of the above-mentioned seed culture solution (4 ml) was added thereto, and the mixture was subjected to rotary shaking culture at 28 ° C and 20 Orpm for 6 days.
- WSS8028 13 C-NMR (CDCls) 6c; 193.6 (s), 192.6 (s), 174.7 (s), 159.5 (s), 154.0 (s), 148.9 (s), 147.0 (s), 146. (s), 144.9 (s), 142.8 (s), 138.3 (s), 133.5 (s), 128.5 (s), 125.5 (d), 125.5 (s), 122. (s), 121.2 (d), 119.4 (s), 115.1 (s), 100.5 (d), 91.6 (t), 75.7 (s), 68.9 (d), 64.3 (d), 61.6 (q), 54.9 (d), 32.2 (q), 22.4 (t), 22.2 (d).
- WSS8003 13 C-NMR (CDCh) 5c; 197.3 (s), 192. (s), 174.6 (s), 159.3 (s), 153.8 (s), 148.9 (s), 147.5 (s), 146.1 (s ), 144.9 (s), 142.8 (s), 138.l (s), 133.5 (s), 128.5 (s), 126.l (s), 125.5 (d), 122. (s), 121.2 (d ), 119.3 (s), 115.2 (s), 101.1 (d), 91.7 (t), 77.3 (s), 69.2 (d), 64.2 (d), 61.6 (d), 56.1 (s), 32.1 (q ), 31.7 (t), 22.2 (q), 21.3 (q) 0
- WSS8028 and WSS8003 are represented by the formula ( ⁇ ) in which R 1 is hydrogen, R 2 is a methyl group, 1 A— is a structure of the formula ( ⁇ ), R 1 is a methyl group, R 2 Is a methyl group, and — A— has the structure of formula ( ⁇ ).
- Example 3
- WSS8029 13C -NMR (CDC ") 6c; 194.7 (s), 193.l (s), 181.3 (s), 163.8 (s), 162.4 (s), 149.9 (s), 149.0 (s), 145.2 (s), 143.8 (s), 143.l (s), 135.0 (s), 133. (s), 131.5 (s), 125.9 (d), 120.5 (d), 120.2 (s), 115.5 (s ), 112.9 (d), 111.3 (s), 107.5 (d), 91.6 (t), 76.l (s), 69.4 (d), 61.7 (d), 55.l (q), 54.7 (d) , 24.9 (q), 23.4 (t).
- WSS8030 13 C-NMR (CDCls) 6c; 193.5 (s), 193.0 (s), 174.6 (s), 163.3 (s), 162.5 (s), 148.9 (s), 147.0 (s), 144.9 (s) , 143.2 (s), 142.8 (s), 138.4 (s), 133.5 (s), 128.3 (s), 125.5 (d), 125.l (s), 122. (s), 121.2 (d), 115.0 (s), 113.3 (s), 111.1 (d), 91.7 (t), 75.9 (s), 68.8 (d), 64.0 (q), 61.6 (q), 54.7 (d), 24.9 (q), 22.6 (t).
- WSS8029 and WSS8030 show that, in the formula (R), R 1 is hydrogen, R 2 is a hydrogen group, 1 A— is a structure of the formula (IV), R 1 is hydrogen, R 2 Has been determined to be a methyl group, and —A— has the structure of formula (IV).
- Test example 1 shows that, in the formula (R), R 1 is hydrogen, R 2 is a hydrogen group, 1 A— is a structure of the formula (IV), R 1 is hydrogen, R 2 Has been determined to be a methyl group, and —A— has the structure of formula (IV). Test example 1.
- WSS2138 was dissolved in DMSO to a concentration of 1 Omg / ml and diluted with sterile water to the desired concentration. (Test cell)
- WSS2138, WSS8003, WSS8028, WSS8029 and WSS8030 were dissolved in DMSO to a concentration of 1 Omg / m 1 and diluted with sterile water to the desired concentration.
- Inhibition rate (%) 100— [ ⁇ (value of group without drug-value of group with drug added) value of group without drug ⁇ X 100]
- the compound of the present invention has a growth inhibitory effect on KB cells and HL-60 cells, it is useful as an antitumor agent.
- FIG. 1 shows the infrared absorption spectrum of WSS2138 measured by the KBr method.
- FIG. 2 shows the 1 H-NMR spectrum of WSS2138 measured at 500 MHz in deuterated dimethyl sulfoxide.
- FIG. 3 shows the 13 C-NMR spectrum of WSS2138 measured in deuterated dimethyl sulfoxide at 125 MHz.
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Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2001292303A AU2001292303A1 (en) | 2000-09-29 | 2001-09-28 | Xanthone compound |
JP2002530773A JPWO2002027010A1 (ja) | 2000-09-29 | 2001-09-28 | キサントン系化合物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2000298572 | 2000-09-29 | ||
JP2000-298572 | 2000-09-29 |
Publications (1)
Publication Number | Publication Date |
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WO2002027010A1 true WO2002027010A1 (fr) | 2002-04-04 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP2001/008566 WO2002027010A1 (fr) | 2000-09-29 | 2001-09-28 | Compose a base de xanthone |
Country Status (3)
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JP (1) | JPWO2002027010A1 (fr) |
AU (1) | AU2001292303A1 (fr) |
WO (1) | WO2002027010A1 (fr) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1550700A (en) * | 1975-05-20 | 1979-08-15 | Ciba Geigy Ag | Antibiotic and processes for its manufacture |
JPS63188394A (ja) * | 1987-01-30 | 1988-08-03 | Mitsubishi Kasei Corp | 多環性キサントン系化合物の製造法 |
JPH02167092A (ja) * | 1988-12-19 | 1990-06-27 | Kirin Brewery Co Ltd | リソリピンxを含む抗腫瘍剤およびリソリピンxの製造法 |
JPH0426625A (ja) * | 1990-05-22 | 1992-01-29 | Banyu Pharmaceut Co Ltd | リゾリピン類を有効成分とする抗腫瘍剤 |
EP0512522A1 (fr) * | 1991-02-26 | 1992-11-11 | Hoechst Aktiengesellschaft | Composés antibiotiques et leur production |
-
2001
- 2001-09-28 AU AU2001292303A patent/AU2001292303A1/en not_active Abandoned
- 2001-09-28 WO PCT/JP2001/008566 patent/WO2002027010A1/fr active Application Filing
- 2001-09-28 JP JP2002530773A patent/JPWO2002027010A1/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1550700A (en) * | 1975-05-20 | 1979-08-15 | Ciba Geigy Ag | Antibiotic and processes for its manufacture |
JPS63188394A (ja) * | 1987-01-30 | 1988-08-03 | Mitsubishi Kasei Corp | 多環性キサントン系化合物の製造法 |
JPH02167092A (ja) * | 1988-12-19 | 1990-06-27 | Kirin Brewery Co Ltd | リソリピンxを含む抗腫瘍剤およびリソリピンxの製造法 |
JPH0426625A (ja) * | 1990-05-22 | 1992-01-29 | Banyu Pharmaceut Co Ltd | リゾリピン類を有効成分とする抗腫瘍剤 |
EP0512522A1 (fr) * | 1991-02-26 | 1992-11-11 | Hoechst Aktiengesellschaft | Composés antibiotiques et leur production |
Non-Patent Citations (5)
Title |
---|
BOCKHOLT H. ET AL.: "Biosynthetic studies on the xanthone antibiotics lysolipins X and I", J. ORG. CHEM., vol. 59, no. 8, 1994, pages 2064 - 2069, XP002907290 * |
DOBLER M. ET AL.: "19. Metabolites of microorganisms. 162nd communication(1). The crystal and molecular structure of lysolipin I", HELV. CHIM. ACTA, vol. 60, no. 1, 1977, pages 178 - 185, XP002907291 * |
DUTHALER R.O. ET AL.: "206. Experiments on the total synthesis of lysolipin I", HELV. CHIM. ACTA, vol. 67, no. 7, 1984, pages 1755 - 1766, XP002907292 * |
DUTHALER R.O. ET AL.: "207. Experiments on the total synthesis of lysolipin I", HELV. CHIM. ACTA, vol. 67, no. 7, 1984, pages 1767 - 1775, XP002907293 * |
KOBAYASHI K. ET AL.: "Actinoplanones C,D,E,F and G, new cytotoxic polycyclic xanthones from actinoplanes sp.", J. ANTIBIOT., vol. 41, no. 6, 1988, pages 741 - 750, XP002907289 * |
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AU2001292303A1 (en) | 2002-04-08 |
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