新型环丙烷酰胺类小分子微管稳定剂的合理设计、合成和抗肿瘤活性研究

Microtubule stabilizing drugs, such as paclitaxel, play an important role in cancer chemotherapy for various human malignancies. In our previous study, a series of novel cyclopropylamide analogues were designed and synthesized. Some of them showed good tubulin polymerization efficiency, in vitro and in vivo antitumor potency, and low toxicity. They also showed similar activity against cell lines that were resistant to paclitaxel. However, their antitumor activity remains to be further improved and the anticancer mechanisms need to be systemically investigated. Inspired by these results, this study aims to discover anticancer NCEs or anticancer candidate drugs with excellent antineoplastic activity and drug-like properties, using rational drug design based on ligand-receptor binding mode, followed by improving antitumor activity and drug-like property simultaneously. As a result, the anticancer mechanisms and in vivo antitumor features of these candidates will be clarified, laying foundations for discovery of innovative, highly effective small molecule microtubule-stabilizing agents with our own intellectual property rights.

以紫杉醇为代表的微管稳定剂在肿瘤治疗中占有重要地位。本课题前期发现一类新型小分子环丙烷酰胺类化合物，具有良好促进微管蛋白聚合能力和体外抗肿瘤活性，初步证实其体内抗肿瘤活性优秀、毒性低，且对紫杉醇耐药肿瘤株仍有较好活性。但是，该类化合物的抗肿瘤活性还有待于进一步提高，它们的抗肿瘤作用机制尚未阐明。因此，本课题基于“药物-靶点”结合模式对先导化合物开展合理药物设计，通过活性和类药性质同步优化策略，获得活性好性质优的抗肿瘤新化学实体或者候选药物。在此基础之上阐明其作用机制和体内抗肿瘤药效特点，为创制具有自主知识产权的高活性小分子微管稳定剂、开发抗肿瘤新药奠定基础。