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STUDIES ON THE ANTIMITOTIC AGENTS-TUBULIN INTERACTION AND DRUG DESIGN

抗有丝分裂剂-微管蛋白相互作用及药物设计的研究

基本信息

批准号：
08407070
负责人：
IWASAKI Shigeo
金额：
$ 12.67万
依托单位：
INSTITUTE OF MOLECULAR AND CELLULAR BIOSCIENCES,THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08407070/
关键词：
antimitotic agent tubulin action mechanism molecular design ustiloxins curacin A arenastatin A

项目摘要

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.

主要研究方向为发现新型抗有丝分裂药物，研究秋水仙碱位点和植物生物碱位点的配体结合的结构-活性关系，以及基于其作用机制模式的新药物和农用化学品的分子设计。在过去的一年里，本项目获得了以下研究成果：(1)从稻稻稻穗上的假黑穗病球中分离到结构最简单的Ustiloxin F，并明确了其结构和抗微管蛋白活性。(2)完成了从海洋蓝藻中分离得到的新型秋水仙碱位点配体curacin A的全合成。本文还合成了各种侧链修饰的类似物，并对其抗微管蛋白和抗菌活性进行了研究。(3)测定了从海绵中分离得到的一种强效细胞毒化合物沙伐他汀A对微管系统的杀伤活性。验证了微管组装（IC_<50>: 2.8 muM）和微管蛋白竞争性结合对根毒素结合的抑制作用。几种合成的arenastatin A类似物对微管组装的活性也进行了评估，结果表明它们的抗微管活性与其对KB细胞的细胞毒性相似。(4)评价了紫杉烷类化合物对Ca^<2+>诱导的微管解聚的微管稳定活性。结果表明，一些缺乏草酸环和酰基侧链的化合物也具有微管稳定活性，而草酸环和酰基侧链是影响紫杉醇生物活性的重要因素。