光活性多靶点铂基抗癌药物的设计合成和构效关系研究

项目名称： 光活性多靶点铂基抗癌药物的设计合成和构效关系研究

项目编号： No.21301181

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： 赵耀

作者单位： 中国科学院化学研究所

项目金额： 25万元

中文摘要： 基于抑制细胞信号传导过程中蛋白激酶活性的靶向抗癌药物是目前抗癌药物研发的前沿和热点；光活化的四价铂细胞毒性抗癌药物为光导向定点清除癌细胞和组织提供了非常有效的方法。本项目拟结合上述两种抗癌药物的优势，探索发展用于癌症综合治疗的多功能靶向组合分子抗癌药物。基本思路是以蛋白酪氨酸激酶抑制剂的衍生物与光活性的四价铂细胞毒性配合物连接，制备兼具分子靶向特性和光细胞毒性的组合分子，发展针对特定肿瘤细胞或组织的靶向多功能组合分子治疗药物。我们将研究设计合成的组合分子在光照和黑暗条件下对特定酪氨酸激酶的抑制作用、组合分子及其光反应产物与DNA的相互作用，结合计算机分子模拟等方法在分子水平上研究组合分子与靶标的相互作用。同时通过研究合成的多功能四价铂组合分子对不同肿瘤细胞的抑制活性，建立组合分子的构效关系，进而优化组合分子的设计和合成，获得具有双重靶向特性的多功能组合分子抗癌药物的先导结构。

中文关键词： 抗癌药物；光激活；铂；多靶点；构效关系

英文摘要： The targeting anticancer drugs for inhibiting the activity of protein kinase in the cellular transduction progress is a leading and hot research area; photoactivated cytotoxic platinum(IV) anticancer drugs provide an effective way for light induced damage to the cancer cells or tissues at the desired area. In this project, we plan to combine the advantages of those two and aim to develop the multi-functional targeting combi-molecules as anticancer drugs for combinational anticancer chemotherapy. The basic idea is to connect the derived protein tyrosine kinase inhibitors with the photoactivatable platinum(IV) cytotoxic metal complexes to produce novel combi-molecules that have both features of molecular targeting and photocytotoxicity, so as to develop multi-functional combi-molecular drugs for specific tumor cells or tissues. We will compare the inhibition activities of combi-molecules towards some tyrosine kinases in the presence/absence of light, study the interaction of them or their photo-products with DNA, and evaluate their interactions with targets using computational molecule models. Meanwhile, we will compare the in vitro anticancer activity of the multifunctional platinum(IV) combi-molecules towards various cancer cell lines, establish the structure-activity relationships, so as to op

英文关键词： Anticancer Agents；Photoactivation；Platinum；Multi-targeting；Structure-activity relationship