STUDY ON THE MICROBIAL METABOLITRES AS THE MEDICINAL RESOURCES

该合作研究项目旨在从微生物代谢产物中探索药用资源，微生物是无限数量的新型生物活性化合物的生产者。本研究主要取得了以下成果：筛选出了干扰微管功能的微生物产物，分离出了稻曲菌素。它们与微管蛋白的相互作用已经阐明（IWASAKI）。建立了一种通用的合成多肽TS-Bs的方法。推导了生物膜和脂质双层中肽的离子通道形成机制（FUJITA）。从蘑菇提取物中分离得到几个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，并检查了构效关系（NOZOE）。从子囊菌的代谢产物中分离得到15个新的单胺氧化酶（MAO）抑制化合物。研究了它们的结构和结构-活性关系（YAMAZAKI）。用培养的中国仓鼠V79细胞证实了合成和天然雌激素对微管的破坏作用，并与其细胞毒性和生长抑制活性（SATO）相关。发现了神经发生诱导剂lactacystin和gp 120-CD 4结合抑制剂isochromophilone I、II和WK-3419 B（TANAKA）。通过放射性标记前体（NAKAGAWA）的饲养实验，研究了乳胞素的生物合成途径及其立体化学特征。基于1，3-多元醇的收敛合成，立体选择性地合成了五霉素的多元醇链段。完成了霉酰菌胺A右半部分的合成，构成了霉酰菌胺的正式全合成。成功地实现了Isaliasinclairii免疫抑制成分ISP-Ⅰ的不对称全合成，合成片段A、B、C的构建及片段间的连接。

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.