STUDIES ON THE ANTIMITOTIC AGENTS-TUBULIN INTERACTION AND DRUG DESIGN

本研究项目的主要内容是：发现新的抗有丝分裂药物，研究秋水仙碱和长春花生物碱位点上结合的配体的构效关系，以及在了解其作用机理的基础上，进行新的医药和农药的分子设计。（1）从水稻（Ina-kouji）的稻曲病菌中分离出了具有最简单结构的稻曲菌素F（Ustiloxin F），并对其结构和有效的抗微管蛋白活性进行了研究。（2）完成了从海洋蓝藻中分离得到的秋水仙碱位点配体curacin A的全合成。还合成了具有修饰侧链的各种类似物，并检查了它们的抗微管蛋白和抗微生物活性。（3）研究了从海绵中分离得到的具有细胞毒活性的化合物arenastatin A对微管系统的抑制作用。验证了微管组装的有效抑制活性（IC：<50>2.8 μ M）和以竞争性方式结合微管蛋白以与根霉素结合。还评价了几种合成的arenastatin A类似物对微管组装的活性，并显示它们的抗微管蛋白活性与它们对KB细胞的细胞毒性平行。（4）研究了从红豆杉中分离的紫杉烷类化合物对Ca^2+诱导的微管解聚的稳定活性。结果表明，作为紫杉醇生物活性的重要组成部分，几种缺少氧杂环和酰基侧链的化合物也表现出微管稳定活性。

The research project concern with the discovery of novel antimitotic agents, studies on the structure-acvtivity relationships of the ligands binding at both the colchicine site and the vinca-alkaloids site, as well as molecular design for new medicinal and agrochemical chemicals, based on the knowledges on the modes of their action mechanisms.In the last year, following results were obtained in this research project : (1)Ustiloxin F,having the simplest structure among ustiloxins, rhizoxin/maytansine site ligands from the false smut balls caused on panicles of rice plant (in Japanese, Ina-kouji), was isolated, and its structure and potent anti-tubulin activity was clarified.(2)Total synthesis of curacin A,a novel colchicine site ligand isolated from marine blue-algae, was accomplished. Various analogues with modified side chains have also been prepared synthetically, and their anti-tubulin and antimicrobial activities were examined.(3)The activity of arenastatin A,a potent cytotoxic compound isolated from marine sponge, against the microtubule system was evaluated. A potent inhibitory activity of microtubule assembly (IC_<50> : 2.8 muM) and binding to tubulin in a competitive manner to rhizoxin binding were verified. Activities of several synthetic analogues of arenastatin A against microtubule assembly were also evaluated, and showed that their anti-tubulin activities were parallel to their cytotoxicity on KB cells.(4)Activities of various Taxane compounds isolated from Japanese Yew Trees were evaluated for microtubule stabilizing actibity against Ca^<2+> induced microtubule depolymerisation. It was shown that several compounds lacking the oxatane ring and the acyl side chain, indicated as the essential factors for the taxol's bioactivity, showed also the microtubule stabilizing actvity.