STUDY ON THE MICROBIAL METABOLITRES AS THE MEDICINAL RESOURCES

该合作研究项目旨在从微生物的代谢物中探索药物资源，微生物是无限数量的新型生物活性化合物的生产者。在研究过程中，积累了以下成果：对干扰微管功能的微生物产物进行了研究，分离出了ustiloxins。它们与微管蛋白的相互作用已被阐明（IWASAKI）。建立了肽类药物TS-Bs的通用合成方法。推断了生物膜和脂质双层中多肽形成离子通道的机制（FUJITA）。从豆豉提取物中分离出了几种具有抗肿瘤活性和谷氨酸受体活性的新化合物。测定了它们的化学结构，并考察了构效关系（NOZOE）。从子囊菌的代谢产物中分离到15个新的单胺氧化酶抑制化合物。研究了它们的结构和构效关系（YAMAZAKI）。人造雌激素和天然雌激素对中国仓鼠V79细胞的破坏作用与细胞毒性和生长抑制活性（SATO）有关。发现了神经发生诱导剂乳糖素（lactacystin）和gp120-CD4结合抑制剂异色嗜色素I、II和WK-3419B （TANAKA）。通过放射性标记前体（NAKAGAWA）的投料实验，研究了乳酸菌素的生物合成途径及其立体化学性质。以1,3-多元醇聚合合成为基础，立体选择性合成了戊霉素多元醇段。完成了mycalamide A右半部分的合成，完成了mycalamide的正式全合成。同时完成了Isalia sinkairii免疫抑制成分ISP-I的全不对称合成，成功构建了合成片段A、B、C并连接了这些片段。

This co-operative research project was organized to explore medicinal resources from the metabolites of microorganisms which are the producers of unlimitted numbers of novel bioactive compounds. In the research therm, the following results have been accumulated.The microbial procducts that interfere with microtubule functions have been searched and ustiloxins were isolated. Their interaction with tubulin have been clarified (IWASAKI). A generic cynthetic method for peptibols, TS-Bs, was established. A ion channel formation mechanism by peptibols in biomembranes and lipid bilayrs was deduced (FUJITA). Several new compounds having antitumor activity and the activities towards glutamate receptor have been isolated from mashroom extracts. Their chemical structures were determined and the structure-activity relationships were examined (NOZOE). Fifteen new monoamine oxidase (MAO)-inhibitory compounds were isolated from the metabolites of Ascomycetes. Their structures and structure-activity relationships were studied (YAMAZAKI). Microtubule disruption by synthetic and natural estrogens were proved by Chinese hamster V79 cells in culture, and were correlated with their cytotoxicity and growth inhibitory activity (SATO). The neurogenesis inducer, lactacystin, and the gp120-CD4 binding inhibitors, isochromophilones I, II and WK-3419B were discovered (TANAKA). Biosynthetic pathway of lactacystin and its stereochemical aspect were investigated by feeding experiments of radio-labeled precursors (NAKAGAWA). Polyol segment of pentamycin was synthesized stereoselectively based on a convergent synthesis of 1,3-polyol. Synthesis of right half of mycalamide A was accomplished, which constututes a formal total synthesis of mycalamide As a total assymmetric synthesis of ISP-I, an immunosuppressive component from Isalia sinclairii, constructuion of the synthetic fragments A,B,C and connection of these fragments were succesfully achieved.