基于糖基结构的新型非膜渗透性碳酸酐酶Ⅸ选择性抑制剂及其抗肿瘤作用机制

碳酸酐酶IX（CA IX）是新型抗肿瘤药物的有效作用靶点之一。本项目针对现有CA IX抑制剂存在的选择性不高这一问题，从CA IX的结构特征和亚细胞定位出发，基于非膜渗透性原理，结合计算机辅助技术预测结果，设计由多种糖基结构修饰的新型CA IX抑制剂，旨在实现对CA IX与其同工酶、肿瘤细胞与正常细胞的双重选择作用。基于课题组扎实的糖化学合成技术，构建新颖的结构多样性化合物库，经酶水平的活性测试，评价选择性抑制CA IX的作用能力，总结较为系统的构效关系。进一步开展细胞渗透率试验、抗肿瘤细胞增殖和抗肿瘤细胞转移实验，验证相应的非膜渗透性靶向作用机制，深入讨论糖基结构的生物学功能，确认CA IX作为抗肿瘤药物靶标的有效性。本项目为建立与肿瘤细胞CA IX产生特异结合和有效作用的抑制剂的发现策略提供一条科学有效的新思路。

Carbonic anhydrases IX (CA IX) has been proved to be one of the effective targets for developing novel antitumor drugs. The proposal aims to achieve novel CA IX inhibitors with high affinity, selectivity and specificity. A series of novel carbohydrate-based CA IX inhibitors were designed on the basis of the latest released principle of membrane impermeability, and will be synthesized via appropriate protective function group strategy. The research approach will be guided by computer-aided design to better fit the inhibitors into the targeting site of CA IX, and their effective binding will contribute to realize a double selectivity both between the CA IX and its isoenzymes, and between the tumor cells and normal cells. Finally, the in vitro penetration rate evaluation, the anti-proliferation and anti-metastasis experiments will be helpful to explore the corresponding mechanism. Projects from this proposed research will ultimately afford new and significant approach to CA IX inhibitors, and seek to go beyond the evident limits of current ones. This will be beneficial to provide new scientific idea for finding CA IX inhibitor leads.