基于片段的靶向拓扑异构酶I抗肿瘤新化学实体的设计、结构优化及其活性研究

拓扑异构酶 I (Topo I)在抗肿瘤新药研发中占有重要的地位。在癌症对人类危害日益严重的今天,通过药物分子的合理设计及构效关系研究, 筛选出更多靶向Topo I的新化学实体，以最终开发出更多高效低毒、疗效稳定的抗肿瘤新药，具有非常重要的意义。 我们以前期提出的"平面结构单元与亲水侧链单元组合"的化合物设计思路为基础，通过前一个课题的研究，找到了"平面结构单元与亲水侧链单元"的合理连接方式，确定了氨基上带有一条合适亲水侧链的4-氨基喹啉可作为一个设计新型拓扑异构酶I抑制剂（或毒化剂）的优势结构片段。我们将这一结构片段与苯并五元杂环组合，发现了一个具有良好抗肿瘤活性的新化学实体，合成了一批抗肿瘤活性与喜树碱相当的新化合物。本研究项目主要是对这一新化学实体进行结构优化，通过对目标化合物进行比较系统深入的构效关系研究，从中筛选出若干活性强、类药性好、具有良好抗肿瘤药用前景的候选化合物。

Topoisomerase I (Topo I) represents a promising and very important molecular target of anticancer agents. The identification of more and more new chemical entities (NCEs) targeted to Topo I and to develop them into more effective antitumor drugs in the guide of rational drug design and SAR/QSAR study, are really a pressing need today when more and more peoples suffering from cancer. Based on the envisage that it would be a rational way to coin novel Topo I-targeted scaffolds by combination a flat planar moiety with a hydrophilic side chain, and our recent studies supported by the previous grants from NSFC, we discovered a rational assemble pattern of the flat planar moiety with the hydrophilic side chain and indentified that the 4-aminoquinoline with an appropriate hydrophilic side chain could serve as a privileged fragments in the design of novel Topo I-targeted scaffolds.And then the 4-aminoquinoline moiety was used to combine with benzimidazole or its bioisoesters to result in new chemical entities (NCEs) with potent anticancer activity. These findings motivate us to put up the research project to structural optimization of the NCEs and to conduct a systematic SAR/QSAR study in the hope of identification several promising candidates for further research.