靶向微管蛋白秋水仙碱位点的白藜芦醇-Combrestatin A-4类抑制剂的设计、合成及活性研究

项目名称： 靶向微管蛋白秋水仙碱位点的白藜芦醇-Combrestatin A-4类抑制剂的设计、合成及活性研究

项目编号： No.21302036

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 阮班锋

作者单位： 合肥工业大学

项目金额： 25万元

中文摘要： 微管是细胞骨架的主要成分，微管蛋白抑制剂（TI）能通过抑制微管蛋白动力学使细胞分裂终止于G2/M期，诱导细胞凋亡。因此，微管（蛋白）是寻找抗肿瘤药物的一个有效靶点。本项目根据"拼合原理"和"基于结构的药物设计"理念，将具有良好抗肿瘤活性的天然产物白藜芦醇（Resveratrol,RES）和微管蛋白秋水仙碱位点抑制剂Combrestatin A-4(CA-4)杂合，创造性地设计出RES-CA-4型微管蛋白抑制剂。拟借助RES、CA-4两个片段在活性位点上的互补性来提高目标分子的活性；通过QSAR和结合模式的研究来指导结构优化；从体内外抗肿瘤活性、微管蛋白抑制活性、细胞周期阻滞、急性毒性等多个角度综合评价目标化合物的药理活性。力争获得高效低毒、低耐药性的新型微管蛋白抑制剂1-2个，为最终开发具有自主知识产权的抗肿瘤药物奠定基础。本项目将为TI研究提供新思路，对新型抗肿瘤药物的研究有重大意义。

中文关键词： 微管蛋白；秋水仙碱位点；白藜芦醇；康普瑞丁；抗肿瘤

英文摘要： Microtubules are cytoskeletal filaments consisting of α,β-tubulin heterodimers and are involved in a wide range of cellular functions that are critical to the life cycle of the cell. Tubulin inhibitors (TI) can cause cell death by cell cycle arrest. Therefore, microtubule is a potent target for screening antitumor drugs. A number of naturally occurring compounds, such as combretastatin A-4(CA-4), paclitaxel, vinblastine and podophyllotoxin, all exhibit their anticancer properties by interfering with the dynamics of tubulin polymerization or depolymerization, resulting in mitotic arrest. Resveratrol (RES), another famous natural product that is well-known for its cancer chemopreventive activity, was found to exhibit antitubulin activity in our group. According to the Combination Principle and the Structure-Based Drug Design, a novel class of tubulin inhibitor, RES-CA-4 (Resveratrol-combrestatin A-4) was designed by confusing Resveratrol and CA-4. Inhibitory activity of the combined molecule will be expected to significantly increase by means of the complementary binding of Resveratrol and CA-4 segments at the colchicine activie site. The structural optimization will be guided by QSAR and binding model; the pharmacological activity of the target molecules will be evaluated by in vitro and in vivo antitumor activi

英文关键词： tubulin；colchicine site；resveratrol；combrestatin-4；antitumor