JPH04282395A - New physiologically active substance ta-3,037a and production thereof - Google Patents
New physiologically active substance ta-3,037a and production thereofInfo
- Publication number
- JPH04282395A JPH04282395A JP4338591A JP4338591A JPH04282395A JP H04282395 A JPH04282395 A JP H04282395A JP 4338591 A JP4338591 A JP 4338591A JP 4338591 A JP4338591 A JP 4338591A JP H04282395 A JPH04282395 A JP H04282395A
- Authority
- JP
- Japan
- Prior art keywords
- active substance
- physiologically active
- substance
- etoh
- glutathione transferase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000013543 active substance Substances 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 102000005720 Glutathione transferase Human genes 0.000 claims abstract description 17
- 108010070675 Glutathione transferase Proteins 0.000 claims abstract description 17
- 241000894006 Bacteria Species 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 241000187747 Streptomyces Species 0.000 claims abstract description 10
- 238000000862 absorption spectrum Methods 0.000 claims abstract description 6
- 238000012258 culturing Methods 0.000 claims abstract description 6
- 238000000354 decomposition reaction Methods 0.000 claims abstract description 4
- 238000002844 melting Methods 0.000 claims abstract description 4
- 230000008018 melting Effects 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract 6
- INMSMQQFIAUCNQ-XFXZXTDPSA-N (3z)-3-benzylidene-2-oxo-4h-1,4-benzoxazine-5-carboxylic acid Chemical compound N1C=2C(C(=O)O)=CC=CC=2OC(=O)\C1=C\C1=CC=CC=C1 INMSMQQFIAUCNQ-XFXZXTDPSA-N 0.000 claims description 35
- 239000003558 transferase inhibitor Substances 0.000 claims description 6
- 229940123468 Transferase inhibitor Drugs 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 abstract description 42
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 201000011510 cancer Diseases 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 206010059866 Drug resistance Diseases 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 230000031700 light absorption Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 11
- 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 10
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 229940041181 antineoplastic drug Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 229940009456 adriamycin Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000186361 Actinobacteria <class> Species 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 241001529936 Murinae Species 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010024636 Glutathione Proteins 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000012136 culture method Methods 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 102220139156 rs774350715 Human genes 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- GMKMEZVLHJARHF-WHFBIAKZSA-N LL-2,6-diaminopimelic acid Chemical compound OC(=O)[C@@H](N)CCC[C@H](N)C(O)=O GMKMEZVLHJARHF-WHFBIAKZSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 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
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 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
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- -1 malates Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940075427 peptone,dried Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 238000011218 seed culture Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Compounds Of Unknown Constitution (AREA)
Abstract
Description
【0001】0001
【産業上の利用分野】本発明は、グルタチオントランス
フェラーゼ阻害活性を有する新規生理活性物質TA−3
037A、その製造法及びそれを含有する薬剤に関する
。[Field of Industrial Application] The present invention provides a novel physiologically active substance TA-3 having glutathione transferase inhibitory activity.
037A, its production method and drugs containing it.
【0002】0002
【従来の技術】抗癌剤を用いた癌化学療法では抗癌剤耐
性細胞の出現が治療上の大きな障壁となってきている。BACKGROUND OF THE INVENTION In cancer chemotherapy using anticancer drugs, the emergence of anticancer drug-resistant cells has become a major therapeutic barrier.
【0003】なかでも、シスプラチンやアルキル化剤に
耐性となった癌細胞では、細胞内グルタチン濃度の増大
とグルタチオントランスフェラーゼ活性の亢進が観察さ
れている〔Cancer Chemother.Ph
armacol.,第17巻,第223〜第226頁(
1986);Biochem.Pharmacol.,
第34巻,第2583〜2586頁(1985)〕。In particular, in cancer cells that have become resistant to cisplatin and alkylating agents, increased intracellular glutatine concentration and enhanced glutathione transferase activity have been observed [Cancer Chemother. Ph
armacol. , Vol. 17, pp. 223-226 (
1986); Biochem. Pharmacol. ,
Volume 34, pages 2583-2586 (1985)].
【0004】従来は、カルシウム拮抗剤を用いて抗癌剤
の細胞内濃度を高めたり、グルタチオン生合成阻害剤を
用いて抗癌剤の不活化機構を阻害するという試みがなさ
れていたが、どれも副作用と効果の点で満足できるもの
ではなく、癌の抗癌剤耐性機構を打ち砕く手段はなかっ
た。Conventionally, attempts have been made to increase the intracellular concentration of anticancer drugs using calcium antagonists and to inhibit the inactivation mechanism of anticancer drugs using glutathione biosynthesis inhibitors, but these efforts have had side effects and effects. This was not satisfactory in that respect, and there was no means to defeat the anticancer drug resistance mechanism of cancer.
【0005】[0005]
【発明が解決しようとする課題】本発明は、抗癌剤の不
活化に関わるグルタチオントランスフェラーゼの阻害物
質、その製造法及びそれを含有する薬剤を提供すること
を目的とするものである。SUMMARY OF THE INVENTION An object of the present invention is to provide an inhibitor of glutathione transferase involved in the inactivation of anticancer drugs, a method for producing the same, and a drug containing the same.
【0006】[0006]
【課題を解決するための手段】本発明を概説すれば、本
発明の第1の発明は、下記理化学的性質を有する新規生
理活性物質TA−3037A(以下TA−3037A物
質という)及びその塩に関するものである。
(1)分子量 281
(2)分子式 C16
H11O4 N1 (3)融点
248〜250℃(分解)
(4)旋光度 〔α〕
D 23=0°(C0.5,DMF)[Means for Solving the Problems] To summarize the present invention, the first invention relates to a novel physiologically active substance TA-3037A (hereinafter referred to as TA-3037A substance) having the following physicochemical properties and a salt thereof. It is something. (1) Molecular weight 281
(2) Molecular formula C16
H11O4 N1 (3) Melting point
248-250℃ (decomposition) (4) Optical rotation [α]
D23=0° (C0.5, DMF)
【0007】(5)紫外吸収スペクトルλmax nm
(ε) 204(26816),242(15674
),282(9385),383(14561),(E
tOH)(5) Ultraviolet absorption spectrum λmax nm
(ε) 204 (26816), 242 (15674
), 282 (9385), 383 (14561), (E
tOH)
【0008】λmax nm(ε) 205(219
97),241(18307),282(9043),
350sh(8615),382(14345)(0.
1N HCl 90% EtOH)λmax n
m(ε) 324(9152)(0.1N NaO
H 90% EtOH)(6)赤外線吸収スペクト
ル(KBr Disk)(cm−1)
3440(br),2930,1752,1663,1
275,1258,758[0008]λmax nm(ε) 205(219
97), 241 (18307), 282 (9043),
350sh (8615), 382 (14345) (0.
1N HCl 90% EtOH) λmax n
m(ε) 324 (9152) (0.1N NaO
H 90% EtOH) (6) Infrared absorption spectrum (KBr Disk) (cm-1) 3440 (br), 2930, 1752, 1663, 1
275,1258,758
【0009】(7) 1H−NMRスペクトル(重DM
SO中、400MHz)(ppm,多重度)6.65(
1H,s),6.90(1H,t),7.32(1H,
dd),7.34(1H,t),7.46(2H,t)
,7.60(2H,d),7.66(1H,dd),1
1.1(1H,s)(7) 1H-NMR spectrum (heavy DM
in SO, 400 MHz) (ppm, multiplicity) 6.65 (
1H, s), 6.90 (1H, t), 7.32 (1H,
dd), 7.34 (1H, t), 7.46 (2H, t)
,7.60(2H,d),7.66(1H,dd),1
1.1 (1H, s)
【0010】(8)13C−NMRスペクトル(重DM
SO中、100MHz)(ppm,多重度)109.4
d,112.0s,118.7d,120.4d,12
3.3s,126.7d,127.8d,128.0d
×2,129.0d×2,129.9s,134.0s
,140.3s,157.3s,169.3s(8) 13C-NMR spectrum (heavy DM
in SO, 100MHz) (ppm, multiplicity) 109.4
d, 112.0s, 118.7d, 120.4d, 12
3.3s, 126.7d, 127.8d, 128.0d
×2,129.0d×2,129.9s,134.0s
, 140.3s, 157.3s, 169.3s
【0011】本発明の第2の発明はTA−3037A物
質の製造法に関する発明であって、ストレプトミセス属
に属するTA−3037A物質生産菌を培養し、その培
養物からTA−3037A物質を採取することを特徴と
するTA−3037A物質の製造法に関するものである
。本発明の第3の発明は、TA−3037A物質又はそ
の塩を有効成分とするグルタチオントランスフェラーゼ
阻害剤に関するものである。The second invention of the present invention relates to a method for producing TA-3037A substance, in which a TA-3037A substance-producing bacterium belonging to the genus Streptomyces is cultured, and the TA-3037A substance is collected from the culture. The present invention relates to a method for producing a TA-3037A substance characterized by the following. The third invention of the present invention relates to a glutathione transferase inhibitor containing TA-3037A substance or a salt thereof as an active ingredient.
【0012】本発明者らは、グルタチオントランスフェ
ラーゼ阻害物質を広く自然界から検索し、アドリアマイ
シン耐性マウス白血病細胞のグルタチオントランスフェ
ラーゼ阻害活性を顕著に示す物質、TA−3037A物
質を得て本発明を完成した。The present inventors have extensively searched nature for glutathione transferase inhibitors, and have completed the present invention by obtaining substance TA-3037A, a substance that exhibits significant glutathione transferase inhibitory activity in adriamycin-resistant murine leukemia cells.
【0013】本発明で使用するTA−3037A物質生
産菌はストレプトミセス属に属し、TA−3037A物
質を生産するものであれば特に制限はないが、その1例
は1988年11月12日、群馬県日光市茶木平で採取
した土壌より分離されたストレプトミセス(Strep
tomyces)属に属する菌株TA−3037があげ
られる。その菌学的特徴は次の通りである。尚、この菌
株は工業技術院微生物工業技術研究所に1991年(平
成3年)2月7日に寄託され、受託番号として微工研菌
寄第11991号(FERM P−11991)が付
与されている。The TA-3037A substance-producing bacteria used in the present invention belongs to the genus Streptomyces, and is not particularly limited as long as it produces the TA-3037A substance. Streptomyces isolated from soil collected at Chakidaira, Nikko City, Prefecture.
strain TA-3037, which belongs to the genus P. tomyces. Its mycological characteristics are as follows. This strain was deposited with the Institute of Microbial Technology, Agency of Industrial Science and Technology on February 7, 1991, and was given the accession number FERM P-11991. There is.
【0014】TA−3037A物質生産菌TA−303
7株は、菌糸巾1ミクロン内外の放線菌であり、光学顕
微鏡下では放線菌の気菌糸上の胞子鎖はRectusf
lexibilisである。電子顕微鏡では桿状の胞子
が観察され、胞子表面は平滑である。細胞壁の構成成分
としては、L,L−ジアミノピメリン酸が検出され、電
顕でも胞子のうやその他の特徴的な構造は認められない
。以上より本菌はストレプトマイセス属に属する。TA-3037A substance producing bacteria TA-303
The 7 strains are actinomycetes with a hyphae width of around 1 micron, and under an optical microscope, the spore chains on the aerial hyphae of actinomycetes are Rectusf.
lexibilis. Rod-shaped spores are observed under an electron microscope, and the spore surface is smooth. L,L-diaminopimelic acid was detected as a component of the cell wall, and no spores or other characteristic structures were observed even under an electron microscope. From the above, this bacterium belongs to the genus Streptomyces.
【0015】本菌の培養性状、生理学的性状ならびに糖
の資化性能の有無を以下の表に示す。尚、各種培地にお
ける色の記載について( )内に示す標準はコンティ
ナー・コーポレーション・オブ・アメリカのカラーハー
モニーマニアルを用いた。すべての性状試験は27℃に
おいて2週間培養後判定した。The culture properties, physiological properties, and sugar assimilation ability of this bacterium are shown in the table below. Regarding the description of colors in various media, the standards shown in parentheses are the Color Harmony Manual of Container Corporation of America. All property tests were determined after culturing for 2 weeks at 27°C.
【0016】[0016]
【表1】[Table 1]
【0017】[0017]
【表2】[Table 2]
【0018】[0018]
【表3】[Table 3]
【0019】以上の性状は本菌が放線菌ストレプトミセ
ス属に属することを示す。従って、本発明で用いるTA
−3037A生産菌は菌株TA−3037と同等または
類縁のストレプトミセス属の放線菌を包含する。The above properties indicate that this bacterium belongs to the genus Streptomyces. Therefore, the TA used in the present invention
-3037A-producing bacteria include actinomycetes of the genus Streptomyces that are equivalent to or related to strain TA-3037.
【0020】TA−3037A物質は、以下に示す理化
学的性状および生物学的性質により特徴づけられる。
(A)TA−3037A物質の理化学的性状(1)分子
量 281(2)分子
式 C16H11O4
N1 (3)融点
248〜250℃(分解)
(4)旋光度 〔α〕
D 23=0°(C0.5,DMF)The TA-3037A substance is characterized by the following physicochemical and biological properties. (A) Physical and chemical properties of TA-3037A substance (1) Molecular weight 281 (2) Molecular formula C16H11O4
N1 (3) Melting point
248-250℃ (decomposition) (4) Optical rotation [α]
D23=0° (C0.5, DMF)
【0021】(5)紫外吸収スペクトルλmax nm
(ε) 204(26816),242(15674
),282(9385),383(14561)(Et
OH)(5) Ultraviolet absorption spectrum λmax nm
(ε) 204 (26816), 242 (15674
), 282 (9385), 383 (14561) (Et
OH)
【0022】λmax nm(ε) 205(219
97),241(18307),282(9043),
350sh(8615),382(14345)(0.
1N HCl 90% EtOH)λmax n
m(ε) 324(9152)(0.1N NaO
H 90% EtOH)λmax nm(ε) 205(219
97), 241 (18307), 282 (9043),
350sh (8615), 382 (14345) (0.
1N HCl 90% EtOH) λmax n
m(ε) 324 (9152) (0.1N NaO
H90% EtOH)
【0023】(6)赤外線
吸収スペクトル(KBr Disk)(cm−1)
3440(br),2930,1752,1663,1
275,1258,758(6) Infrared absorption spectrum (KBr Disk) (cm-1) 3440 (br), 2930, 1752, 1663, 1
275,1258,758
【0024】(7) 1H−NMRスペクトル(重DM
SO中、400MHz)(ppm,多重度)6.65(
1H,s),6.90(1H,t),7.32(1H,
dd),7.34(1H,t),7.46(2H,t)
,7.60(2H,d),7.66(1H,dd),1
1.1(1H,s)(7) 1H-NMR spectrum (heavy DM
in SO, 400 MHz) (ppm, multiplicity) 6.65 (
1H, s), 6.90 (1H, t), 7.32 (1H,
dd), 7.34 (1H, t), 7.46 (2H, t)
,7.60(2H,d),7.66(1H,dd),1
1.1 (1H, s)
【0025】(8)13C−NMRスペクトル(重DM
SO中、100MHz)(ppm,多重度)109.4
d,112.0s,118.7d,120.4d,12
3.3s,126.7d,127.8d,128.0d
×2,129.0d×2,129.9s,134.0s
,140.3s,157.3s,169.3s
(9)外観
黄色針状結晶。(8) 13C-NMR spectrum (heavy DM
in SO, 100MHz) (ppm, multiplicity) 109.4
d, 112.0s, 118.7d, 120.4d, 12
3.3s, 126.7d, 127.8d, 128.0d
×2,129.0d×2,129.9s,134.0s
, 140.3s, 157.3s, 169.3s (9) Appearance yellow needle-like crystals.
【0026】(B)TA−3037A物質の生物学的性
状
(1)抗菌活性
寒天希釈法において、TA−3037A物質は、各種細
菌、かびなどに対し50μg/mlでそれらの増殖を阻
止しなかった。(B) Biological properties of TA-3037A substance (1) Antibacterial activity In the agar dilution method, TA-3037A substance did not inhibit the growth of various bacteria and molds at 50 μg/ml. .
【0027】(2)急性毒性
TA−3037A物質のマウスに対する急性毒性を試験
した結果、マウス腹腔内投与の場合100mg/kgで
毒性を示さなかった。(2) Acute toxicity As a result of testing the acute toxicity of the substance TA-3037A to mice, it showed no toxicity when administered intraperitoneally to mice at 100 mg/kg.
【0028】(3)生理活性
TA−3037A物質のグルタチオントランスフェラー
ゼ阻害活性の測定はHabigらの方法〔J.Biol
.Chem.,第249巻,第7130〜7139頁(
1974)〕に準じて行なった。すなわち、100mM
リン酸カリウム緩衝液(pH6.5)に1mMグルタチ
オンと1mMクロロジニトロベンゼンを含む反応液に、
検体と酵素液を添加した際の、30℃における340n
mの吸光度の増加を測定した。酵素液はアドリアマイシ
ン耐性マウス白血病細胞の細胞破砕液を用いた。その結
果、TA−3037A物質のアドリアマイシン耐性マウ
ス白血病細胞のグルタチオントランスフェラーゼに対す
る50%阻害濃度は、2.5μg/mlであった。(3) The glutathione transferase inhibitory activity of the physiologically active TA-3037A substance was measured by the method of Habig et al. [J. Biol
.. Chem. , Volume 249, Pages 7130-7139 (
1974)]. That is, 100mM
To a reaction solution containing 1mM glutathione and 1mM chlorodinitrobenzene in potassium phosphate buffer (pH 6.5),
340n at 30℃ when adding sample and enzyme solution
The increase in absorbance of m was measured. As the enzyme solution, a cell lysate of adriamycin-resistant mouse leukemia cells was used. As a result, the 50% inhibitory concentration of the TA-3037A substance against glutathione transferase of adriamycin-resistant mouse leukemia cells was 2.5 μg/ml.
【0029】以上のごとく、本発明のTA−3037A
物質は、低濃度でアドリアマイシン耐性マウス白血病細
胞のグルタチオントランスフェラーゼを阻害し、抗菌活
性も毒性も極めて弱いことから、癌の薬剤耐性克服剤と
して期待される。TA−3037A物質の塩としては、
例えば通常使用される酸との酸付加塩、あるいはアルカ
リ金属、アルカリ土類金属との塩等の通常汎用されてい
る薬理学的に許容し得る塩が挙げられる。As described above, TA-3037A of the present invention
The substance inhibits glutathione transferase in adriamycin-resistant murine leukemia cells at low concentrations, and has extremely low antibacterial activity and toxicity, so it is expected to be used as an agent to overcome drug resistance in cancer. As the salt of TA-3037A substance,
Examples include commonly used pharmacologically acceptable salts such as acid addition salts with commonly used acids, and salts with alkali metals and alkaline earth metals.
【0030】本発明のTA−3037A物質はTA−3
037A物質生産菌を培養しその培養物から採取するこ
とによって製造することができる。TA−3037A物
質生産菌を培養する際に使用する培地は、TA−303
7A物質生産菌が利用できる任意の栄養源を含有するも
のであれば良い。例えば、炭素源としてグリセリン、グ
ルコース、マルトース、シュクロース、デキストリン、
でんぷん、油脂類などが使用できる。窒素源として大豆
粉、綿実粕、肉エキス、ペプトン、乾燥酵母、酵母エキ
ス、コーンスティープリカーなどの有機物、並びに硝酸
アンモニウム、硝酸ナトリウム、炭酸カルシウム、塩化
アンモニウムなどの無機物が使用できる。The TA-3037A substance of the present invention is TA-3
It can be produced by culturing 037A substance-producing bacteria and collecting from the culture. The medium used when culturing the TA-3037A substance-producing bacteria is TA-303
Any nutrient source that can be used by the 7A substance-producing bacteria may be used. For example, as a carbon source, glycerin, glucose, maltose, sucrose, dextrin,
Starch, fats and oils, etc. can be used. As nitrogen sources, organic substances such as soybean flour, cottonseed meal, meat extract, peptone, dried yeast, yeast extract, and corn steep liquor, as well as inorganic substances such as ammonium nitrate, sodium nitrate, calcium carbonate, and ammonium chloride can be used.
【0031】また、必要に応じて食塩、塩化カリウム、
りんご酸塩、重金属塩などの無機塩類を添加することも
できる。発酵中の発泡を抑制するために、常法に従って
適当な消泡剤、例えばシリコーン、大豆油などを適宜添
加することもできる。[0031] If necessary, salt, potassium chloride,
Inorganic salts such as malates, heavy metal salts, etc. can also be added. In order to suppress foaming during fermentation, an appropriate antifoaming agent such as silicone, soybean oil, etc. may be added according to a conventional method.
【0032】培養法としては、一般に行われている抗生
物質の生産の方法と同様に、好気的液体深部培養法が最
も適している。使用しうる培養温度はTA−3037A
物質生産菌の発育が実質的に阻害されず、TA−303
7A物質を生産しうる範囲であれば、特に制約されるも
のではないが、特に好ましいのは25〜30℃の範囲内
の温度を挙げることができる。As the culture method, an aerobic liquid deep culture method is most suitable, similar to the commonly used method for producing antibiotics. The culture temperature that can be used is TA-3037A.
The growth of substance-producing bacteria is not substantially inhibited, and TA-303
Although there are no particular restrictions as long as the temperature is within a range where the 7A substance can be produced, a particularly preferred temperature range is 25 to 30°C.
【0033】培養時間は、通常、TA−3037A物質
が十分に蓄積するまで継続することができ、培地組成、
培養温度により異なるが、通常48〜96時間の培養で
目的のTA−3037A物質を得ることができる。[0033] The incubation time can generally be continued until sufficient accumulation of the TA-3037A substance, and the culture medium composition,
Although it varies depending on the culture temperature, the desired TA-3037A substance can usually be obtained by culturing for 48 to 96 hours.
【0034】かくして得られる培養物から、TA−30
37A物質を単離するには、合目的的な任意の方法が利
用可能である。例えば、培養物を濾過し、遠心分離など
のそれ自体公知の分離方法によって菌体を除去し、その
濾液上清から適当な有機溶媒を用いた溶媒抽出法や、吸
着やイオン交換能を利用したクロマトグラフィーを単独
で、または組み合わせて使用することにより単離精製し
て採取することができる。From the culture thus obtained, TA-30
Any convenient method can be used to isolate the 37A material. For example, the culture is filtered, the bacterial cells are removed by a separation method known per se, such as centrifugation, and the filtrate supernatant is extracted using a solvent extraction method using an appropriate organic solvent, or by using adsorption or ion exchange ability. It can be isolated and purified using chromatography alone or in combination.
【0035】本発明のTA−3037A物質はグルタチ
オントランスフェラーゼを強く阻害する作用を有する。
従って本発明ではTA−3037A物質又はその塩を有
効成分とするグルタチオントランスフェラーゼ阻害剤が
提供される。グルタチオントランスフェラーゼ阻害剤は
酵素阻害剤等の試薬又は癌の薬剤耐性克服剤などの医薬
として有用である。本発明のグルタチオントランスフェ
ラーゼ阻害剤を癌の薬剤耐性の克服のために使用するに
は、人を含む担癌温血動物にTA−3037A物質の有
効量を投与すればよい。投与方法は注射などの他、経口
投与及び注射以外の非経口投与などの方法で行うことが
できる。投与量は投与する対象、投与ルートなどによっ
て変動するが通常0.1mg〜100mg/kg/日、
好ましくは0.5〜50mg/kg/日程度である。The TA-3037A substance of the present invention has the effect of strongly inhibiting glutathione transferase. Therefore, the present invention provides a glutathione transferase inhibitor containing the substance TA-3037A or a salt thereof as an active ingredient. Glutathione transferase inhibitors are useful as reagents such as enzyme inhibitors or medicines such as agents for overcoming cancer drug resistance. In order to use the glutathione transferase inhibitor of the present invention to overcome drug resistance in cancer, an effective amount of the TA-3037A substance may be administered to cancer-bearing warm-blooded animals including humans. Administration methods include injection, oral administration, and parenteral administration other than injection. The dosage varies depending on the subject to be administered and the route of administration, but is usually 0.1 mg to 100 mg/kg/day.
Preferably it is about 0.5 to 50 mg/kg/day.
【0036】投与する際の製剤としては特に制限はなく
、TA−3037A物質は通常使用される医薬用添加剤
、例えば担体や補助剤などとともに液剤、固型製剤(カ
プセル、錠剤、凍結乾燥製剤など)等として製剤化され
、投与される。以下に、実施例により本発明のTA−3
037A物質の製造例を示し、更に本発明を詳細に説明
するが、本発明はこれら実施例に限定されない。There are no particular restrictions on the formulation for administration, and the TA-3037A substance can be used in liquid formulations, solid formulations (capsules, tablets, lyophilized formulations, etc.) together with commonly used pharmaceutical additives such as carriers and adjuvants. ) etc. and are administered. Hereinafter, TA-3 of the present invention will be explained based on examples.
The present invention will be further explained in detail by showing production examples of the 037A substance, but the present invention is not limited to these examples.
【0037】[0037]
【実施例】寒天斜面培地に培養した放線菌(微工研菌寄
第11991号)をグリセロール2.5%、肉エキス(
極東)0.5%、ポリペプトン(日本製薬)0.5%、
酵母エキス(Difco)1.0%、硫酸マグネシウム
0.05%、炭酸カルシウム0.32%を含む液体培地
(pH7.4に調整)を三角フラスコ(500ml容)
に100mlずつ分注して、常法により120℃で20
分間あらかじめ滅菌しておいたものに接種し、27℃で
72時間回転振盪培養(毎分180回転)した。この種
母培養液を同様に三角フラスコに分注、滅菌した上記の
培地10リットルに2%接種し、27℃で72時間回転
振盪培養した。[Example] Actinomycetes (Feikoken Bibori No. 11991) cultured on agar slant medium were treated with 2.5% glycerol and meat extract (
Far East) 0.5%, polypeptone (Nippon Pharmaceutical) 0.5%,
A liquid medium (adjusted to pH 7.4) containing 1.0% yeast extract (Difco), 0.05% magnesium sulfate, and 0.32% calcium carbonate was added to an Erlenmeyer flask (500 ml volume).
Dispense 100 ml each into
The cells were inoculated into cells that had been previously sterilized for minutes, and cultured with rotary shaking (180 revolutions per minute) at 27°C for 72 hours. This seed culture solution was similarly dispensed into Erlenmeyer flasks, 2% inoculated into 10 liters of the above sterilized medium, and cultured with rotational shaking at 27° C. for 72 hours.
【0038】このようにして得られた培養液を遠心分離
器にかけて菌体を分離した上清9リットルをpH2にし
て等量の酢酸ブチルで抽出した。この抽出液を減圧下に
濃縮し、得られた残渣6.6gをセファデックスLH−
20カラムにかけてメタノールで展開した。この活性画
分を集め減圧下に濃縮して得られた粗粉末206mgを
シリカゲルカラムにかけて、クロロホルム−メタノール
(50:1)で溶出展開した。この活性画分を集め減圧
下に濃縮し、メタノール:クロロホルム=1:1に加温
して溶かして静置すると、結晶化した。こうして、TA
−3037A物質の黄色結晶125mgを得た。The culture solution thus obtained was centrifuged to separate the bacterial cells, and 9 liters of the supernatant was adjusted to pH 2 and extracted with an equal amount of butyl acetate. This extract was concentrated under reduced pressure, and 6.6 g of the resulting residue was added to Sephadex LH-
20 columns and developed with methanol. The active fractions were collected and concentrated under reduced pressure, and 206 mg of the resulting crude powder was applied to a silica gel column and eluted and developed with chloroform-methanol (50:1). The active fractions were collected and concentrated under reduced pressure, heated to dissolve in methanol:chloroform=1:1, and allowed to stand to crystallize. In this way, T.A.
125 mg of yellow crystals of -3037A substance were obtained.
【0039】[0039]
【発明の効果】本発明のTA−3037A物質は、アド
リアマイシン耐性マウス白血病細胞のグルタチオントラ
ンスフェラーゼを強く阻害し、抗菌活性がほとんどなく
、低毒性の抗癌剤耐性克服剤として、癌の治療に期待さ
れる優れた新規物質である。また、本発明によるTA−
3037A物質は、グルタチオントランスフェラーゼ阻
害活性によって、ロイコトリエンの生合成を阻害するア
レルギー疾患治療剤として、使用できる可能性をも有し
ている。本発明はこれら有用な性質を有する新規物質を
提供する極めて有用な発明である。Effects of the Invention The TA-3037A substance of the present invention strongly inhibits glutathione transferase of adriamycin-resistant murine leukemia cells, has almost no antibacterial activity, and is expected to be an excellent agent for cancer treatment as a low-toxic anticancer drug resistance overcoming agent. It is a new substance. Furthermore, the TA-
Substance 3037A also has the possibility of being used as a therapeutic agent for allergic diseases that inhibits leukotriene biosynthesis through its glutathione transferase inhibitory activity. The present invention is an extremely useful invention that provides a new substance having these useful properties.
Claims (3)
とする新規生理活性物質TA−3037A及びその塩:
(1)分子量 281
(2)分子式 C16
H11O4 N1 (3)融点
248〜250℃(分解) (4)旋光度 〔α〕
D 23=0°(C0.5,DMF) (5)紫外吸収スペクトル λmax nm(ε) 204(26816),24
2(15674),282(9385),383(14
561),(EtOH) λmax nm(ε) 205(21997),24
1(18307),282(9043),350sh(
8615),382(14345) (0.1N HCl 90% EtOH)λma
x nm(ε) 324(9152)(0.1N
NaOH 90% EtOH)。Claim 1: A novel physiologically active substance TA-3037A and its salts, characterized by having the following physicochemical properties:
(1) Molecular weight 281
(2) Molecular formula C16
H11O4 N1 (3) Melting point
248-250℃ (decomposition) (4) Optical rotation [α]
D 23 = 0° (C0.5, DMF) (5) Ultraviolet absorption spectrum λmax nm (ε) 204 (26816), 24
2 (15674), 282 (9385), 383 (14
561), (EtOH) λmax nm(ε) 205 (21997), 24
1 (18307), 282 (9043), 350sh (
8615), 382 (14345) (0.1N HCl 90% EtOH) λma
x nm (ε) 324 (9152) (0.1N
NaOH 90% EtOH).
活性物質TA−3037A生産菌を培養しその培養物か
ら新規生理活性物質TA−3037Aを採取することを
特徴とする新規生理活性物質TA−3037Aの製造法
。2. Production of a novel physiologically active substance TA-3037A, which comprises culturing a novel physiologically active substance TA-3037A-producing bacterium belonging to the genus Streptomyces and collecting the novel physiologically active substance TA-3037A from the culture. Law.
はその塩を有効成分とするグルタチオントランスフェラ
ーゼ阻害剤。3. A glutathione transferase inhibitor comprising a novel physiologically active substance TA-3037A or a salt thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4338591A JPH04282395A (en) | 1991-03-08 | 1991-03-08 | New physiologically active substance ta-3,037a and production thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4338591A JPH04282395A (en) | 1991-03-08 | 1991-03-08 | New physiologically active substance ta-3,037a and production thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH04282395A true JPH04282395A (en) | 1992-10-07 |
Family
ID=12662344
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP4338591A Pending JPH04282395A (en) | 1991-03-08 | 1991-03-08 | New physiologically active substance ta-3,037a and production thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH04282395A (en) |
-
1991
- 1991-03-08 JP JP4338591A patent/JPH04282395A/en active Pending
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