抗肝癌天然产物Kadlongilactones类似物的合成与构效关系研究

Multidrug resistance (MDR) mediated by ABC transporters is a major cause of limiting the chemotherapy for liver cancer. The combination of chemotherapeutic drugs and MDR reversal agents is currently the main therapeutic strategy. However, the biggest problem with combination therapies is that most of the traditional MDR reversal agents suffer from insufficient MDR reversal potency or unacceptable side effects. Therefore, it is of great significance to develop anti-hepatoma drugs with high efficiency, low toxicity and MDR reversal potency. Kadlongilactones-type natural products exhibit both inhibitory activity of ABC transporters and good anti-hepatoma activity, so they are potential anti-liver cancer compounds that can reverse MDR. However, the limited source and unknown mechanism of action have restricted their further research and development. On the basis of the completed total synthetic route, this project intends to construct a library of Kadlongilactones' analogues with structural diversity, and then study the structure-activity relationship and the mechanism of action. At the same time, probe molecules will be designed and synthesized to explore the targets of the drugs based on the structure of natural products. The project is expected to obtain novel lead compounds, which will provide a new molecular basis for the design of anti-liver cancer drugs with MDR reversal activity.

由ABC转运蛋白介导的多药耐药性是限制肝癌化疗应用的重要原因，联合使用化疗药物和耐药逆转剂是目前采取的主要治疗策略。然而，联合用药存在一个最大的问题是大部分传统耐药逆转剂效率低，毒副作用大。因此，开发高效低毒的、具有耐药逆转作用的抗肝癌药物具有十分重要的意义。Kadlongilactones类天然产物兼具抑制ABC转运蛋白的活性和较好的抗肝癌活性，是一类非常有潜力的可逆转多药耐药性的抗肝癌化合物。但是其来源有限，作用机制尚不明确，严重制约了进一步的研究与开发。因此，本项目拟在已完成的全合成路线基础上，构建结构多样性的Kadlongilactones类似物库并进行构效关系和作用机制的研究。同时设计合成探针分子，开展基于天然产物结构的抗耐药肝癌药物作用靶点的探索研究。本项目有望获得新型的抗肝癌先导化合物，为设计可逆转多药耐药性的抗肝癌药物提供新的分子基础。

Kadlongilactones类天然产物兼具抑制ABC转运蛋白的活性和较好的抗肝癌活性，是一类非常有潜力的可逆转多药耐药性的抗肝癌化合物。但是其来源有限，作用机制尚不明确，严重制约了进一步的研究与开发。因此，本项目拟在已完成的全合成路线基础上，构建结构多样性的Kadlongilactones类似物库并进行构效关系和作用机制的研究。同时设计合成探针分子，开展基于天然产物结构的抗耐药肝癌药物作用靶点的探索研究。项目执行人发展了以D-A反应和HAT反应为关键反应的合成路线，拓展了具有多环环系结构的天然产物简化物或者类似物的合成策略，进而得到了不同多环环系的天然产物类似物及衍生物共计30个。对所得的部分产物进行了活性测试，并发现了对HepG2和Huh-7肝癌细胞具有抑制活性的衍生物LL-9（IC50分别为3.12 μM和2.12 μM）。初步的作用机制研究表明化合物LL-9能浓度依赖性的诱导肝癌细胞凋亡，并且能够强烈的抑制细胞周期，使细胞周期阻滞在G1期。同时，化合物LL-9还可以抑制细胞的侵袭迁移，引起细胞耐药相关蛋白ABCB1和ABCG2水平的下调。说明该化合物可作为探索逆转MDR的抗肝癌药物的先导化合物。