Development of new drugs based on the metabolic activation by intestinal bacteria.

基于肠道细菌代谢激活的新药开发。

• 批准号: 09557178
• 负责人: HATTORI Masao
• 金额: $ 8.32万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557178/
• 关键词: paeoniflorin; anti-convulsant; ginsenoside; metabolite; intestinal bacteria; Bacteroides; Peptostreptococcus; Eubacterium; アコニチン; リポアコニチン; 抗ケイレン作用; ジンセノシド; レイン; 瀉下薬; ペオニメタボリン; ジンセノシド Rbl; 当帰芍薬散; 芍薬甘草湯; 抗けいれん作用; エピカテキン ガレート; サイコサポニン; B

1. Synthesis of paeonimetabolin derivatives and their anti-convulsant activityBy incubation of paeoniflorin from peony roots with a human intestinal bacterium Lactobacillus brevis in the presence of mercapto compounds, 17 different kinds of paeonimetabolin derivatives were prepared and examined their anti-convulsant activity ; 8-(n-hexylthio)-, 8-cyclopentylthio-, 8-(p-tolylthio)-, and 8-benzoylthiopaeonimetabolin showed potent activity. After separation of the last compound by column chromatography, 7S-derivative showed the most potent anti-convulsant activity, but 7R-derivative showed the muscle relaxation effect.2. Effects of a metabolite of ginsenoside by intestinal bacteria on metastasis and apoptosis of tumor cellsA metabolite (20S)-protopanaxadiol 20-O-glucoside of ginsenoside Rb1 showed potent anti-metastatic action in mice. As to the mechanism of the anti-metastatic action, it was demonstrated that this metabolite induced apoptosis of the tumor cells by modulating apoptosis related proteins such as cyclin D, p27 kip and c-myc etc.3. Development of new reactions mediated by intestinal bacteria.a. Conversion of rhein to rhein anthroneb. Demethylationc. DehydroxylationDuring the investigation under the above project, we islated three bacterial strains Bacteroides sp., Peptostreptococcus sp., and Eubacterium sp., from human feces, which catalyzed the new reactions a-c.

1.丹皮内酯衍生物的合成及其抗惊厥活性通过将牡丹根中的芍药苷与一株人肠道细菌短链乳杆菌在巯基化合物存在下孵育，合成了17种不同的丹皮内酯衍生物，并对其抗惊厥活性进行了研究，其中8-(正己硫基)-8-环戊硫基-8-(对甲苯硫基)-8-苯甲酰硫代谢素显示出较强的抗惊厥活性。最后一种化合物经柱层析分离后，7S-衍生物的抗惊厥活性最强，而7R-衍生物的抗惊厥活性最强。人参皂苷肠道细菌代谢产物(20S)-人参皂苷Rb1的原人参二醇20-O-葡萄糖苷对小鼠肿瘤细胞转移和凋亡的影响显示出较强的抗转移作用。关于抗转移作用的机制，已有研究证明该代谢产物通过调控细胞周期蛋白D、p27kip和c-myc等细胞凋亡相关蛋白诱导肿瘤细胞的凋亡。肠道细菌介导的新反应的发展。将大黄酸转化为大黄酸并冠醚。去甲基化。在上述项目的研究中，我们从人的粪便中分离出三株细菌：类杆菌属、消化链球菌属和真细菌属，它们催化了a-c的新反应。

项目成果

Kida H. et al.: "Metabolism and Pharmacokinetics of Orally Administered Saikosaponin b1 in Conventional, Germ-Free and Eubacterium sp. A-44 Infected Gnotobiote Rats"Biol. Pharm. Bull.. 21. 588-593 (1998)

Kida H. 等人：“传统、无菌和真杆菌属 A-44 感染的知生物大鼠中口服柴胡皂苷 b1 的代谢和药代动力学”Biol。

Abdel-Hafez A. A. et al.: "Anticonvulsant activity of paeonimetabolin-I adducts obtained by incubation of paeoniflorin and thiol compounds with Lactobacillus brevis."Biol. Pharm. Bull.. 22. 491-497 (1999)

Abdel-Hafez A. A. 等人：“通过将芍药苷和硫醇化合物与短乳杆菌一起孵育，获得芍药代谢素-I 加合物的抗惊厥活性。”Biol。

Kawata Y. et al.: "Conversion of aconitine to lipoaconitine by human intestinal bacteria and their antinoceptive effects in mice."J. Trad. Med.. 16. 15-23 (1999)

Kawata Y. 等人：“人类肠道细菌将乌头碱转化为脂乌头碱及其对小鼠的镇痛作用。”J.

Kida H. et al.: "Isolation and identification of human intestinal bacteria capable of hydrolyzing saikosaponins"J. Trad. Med.. 14. 34-40 (1997)

Kida H.等人：“能够水解柴胡皂苷的人体肠道细菌的分离和鉴定”J.

Hasegawa H. et al.: "Synthesis of a biologically active fluorescent derivative of GM1, a main ginseng saponin metabolite formed by intestinal bacteria"Biol. Pharm. Bull.. 21. 513-516 (1998)

Hasekawa H.等人：“GM1的生物活性荧光衍生物的合成，GM1是肠道细菌形成的主要人参皂苷代谢物”Biol。