新型双环氮杂苯基微管蛋白聚合抑制剂的设计、合成及抗肿瘤活性研究

项目名称： 新型双环氮杂苯基微管蛋白聚合抑制剂的设计、合成及抗肿瘤活性研究

项目编号： No.21262043

项目类型： 地区科学基金项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 金毅

作者单位： 云南大学

项目金额： 50万元

中文摘要： 细胞有丝分裂异常是导致肿瘤发生的重要原因之一，参与有丝分裂过程的微管蛋白酶（tubulin）已成为一个重要的抗癌药物作用靶点。在前期研究中，根据tubulin活性部位特点，利用组合库设计及虚拟筛选发现了一类三唑苯脲结构的新颖微管蛋白聚合抑制剂，能有效抑制肿瘤细胞HGC-27与A549的生长，并明显的阻断肿瘤细胞生长于M期。本项目拟在此基础上，用基于片段的分子设计方法和类药性早期评价，对先导化合物T-35进行结构优化，建立三唑苯基脲类似结构母核的合成方法学.设计合成基于双环氮杂苯基结构的系列衍生物，并进行生物活性评价。以期获得结构新颖、高活性、低毒的微管蛋白抑制剂。

中文关键词： 微管蛋白；肿瘤；合成；喹啉；多环噁二唑

英文摘要： Mitosis exception is the important one of the reasons that lead to tumorigenesis. Tubulin plays an important role in tumor development and metastasis, it has become a new anticancer drug target.In preliminary studies, we found a novel triazole phenylurea tubulin polymerization inhibitor which can effectively inhibit the growth of tumor cells HGC-27 and A549, and obviously blocked the growth of tumor cells in M phase by according to the characteristics of tubulin active site and using combinatorial library design and virtual screening. Based on the previous study, lead compounds T-35 will be optimized using fragment-based molecular design method and drug-like evaluation, as well as the similar heterocyclic compounds synthesis methods will be developed. Finally,design and synthesis a series of derivatives based on the bicyclic aza phenyl structure. The biological activity of these compounds will be subsequently evaluated.Hopefully we will find high activity and low toxicity tubulin inhibitors.

英文关键词： tubulin；cancer；synthesis；quilonine；polycyclic-oxadiazole