新型自旋标记喹啉类拓扑异构酶I抑制剂的设计合成及其生物活性研究

本项目拟以确立的3类喹啉类拓扑异构酶I （Top I ）抑制剂分子骨架为修饰与结构优化目标，综合运用有机合成方法、电子等排原理、活性官能团导向设计等分子合成与优化操作，进行多样性自旋标记喹啉类 Top I 抑制剂的设计合成与结构优化研究，并结合细胞毒活性测试，分析探讨其构效关系；同时，以3-5个高活性化合物为供试药剂，开展其抗肿瘤作用机制、体内抗肿瘤活性与毒性评价以及药代动力学研究。在此基础上，进一步以 “嵌合型”自旋标记化合物作为小分子探针进行后续的化学生物学研究，检测和示踪药物分子在肿瘤组织中的代谢分布以及与靶蛋白的作用方式，为进一步详细阐明其抗肿瘤作用机制及生物合理设计新型Top I 抑制剂提供必要的理论依据。

In order to optimize antitumor activity of three quinoline-related chemotype of anticancer compounds, a diverse set of novel spin-labeled topoisomerase I inhibitors based on quinoline chromophore were designed, and synthesized by different protocols such as diverted total synthesis, bioisosteric replacement and privileged active scaffolds combined strategy. Cytotoxicity data from human cancer cell cultures were used to establish structure activity relationships. Simultaneously, the 3-5 representative highly active compounds were selected to investigate mechanisms of action, in vivo antitumor activity, toxicity and pharmacokinetics assay of these synthetic compounds. Furthermore, the visualization of localization and critical transport pathway inside tumor is studied by the application of chemical biology, which is useful in guiding further design of potential novel topoisomerase I inhibitors, as well as contributing to a better understanding of their mechanisms of action.