抗肿瘤二萜salviyunnanone的不对称全合成与构效关系研究

Hunting for medicine to cure Cancer has made the discovery of molecules with new structure and mechanism become a hot issue of global research. As a matter of fact, new mechanism often oriented from compounds with new structure, therefore, new structure is important to the discovery of new mechanism. In previous work, Salviyunanone , a diterpenoid isolated from Salvia farinacea, has shown significant cytotoxicity against several human cancer cell line. Inspired by the structures of anti tumor molecules Triptolide and Erocalyxin B, we regarded that total synthesis and SAR studies of Salviyunnanone can no longer result in the development of new synthetic method, but also can provide enough sample for verification of it biological function, therefore, very important. Recently, we have completed the construction of tricycle intermediate, which showed the good feasibility of this project. We will perform asymmetric total synthesis, launch limited SAR studies against cancer assisted by Computer Aided Drug Design (CADD). The smooth progress of this project will provide general method for the asymmetric construction of tricycle diterpenoid and synthetic methods for epoxyenone unit as well. Furthermore, it is possible to get low toxic and effective molecules after structure optimization. This will pave a solid foundation for further biological mechanism study.

癌症的危害性致使寻找结构与机制新颖的化合物仍是全球关注的热点。实践证明，新的作用机制往往来源于结构新颖的化合物，因此具有活性的新结构对新机制的发现意义重大。前期工作中从鼠尾草中分离的新颖二萜Salviyunnanone在多种人肿瘤细胞株中显示了较好的细胞毒活性，我们在雷公藤甲素，毛萼乙素等重要抗癌活性分子的启发下，认为对Salviyunnanone进行合成和高氧化度等的结构修饰不仅可能发现新的合成方法，还将为进一步的结构优化和功能验证提供足够的样品保证，意义十分明显。新近我们已经完成了三环关键中间体的构建，预示项目的可行性较好。本项目拟开展不对称全合成研究，并采取计算机辅助的药物设计进行定向结构修饰，研究其抗肿瘤构效关系。项目的顺利执行将提供三环二萜骨架的通用不对称合成策略及环氧烯酮结构的合成方法，可能优化出高效低毒的活性分子，为进一步的作用机制研究打下坚实基础。

癌症是我国的主要致死因素，其抗肿瘤研究成为全球关注的热点。在二萜天然产物雷公藤甲素，毛萼乙素等抗癌活性分子的启发下，本项目按计划开展了抗肿瘤二萜Salviyunnanone的全合成和高氧化度等结构修饰的研究，并对衍生物进行活性筛选。经过四年的努力，开展了所有的研究内容，包括全合成与构效关系。取得了进展如下，开发了6/5/6,6/6/6,7/5/6等三环骨架构建的新方法，并应用到衍生物合成中，按计划合成了37个衍生物，活性测试表明无明显规律，其C6 差向异构体的活性较好。.发表原创性研究论文2篇，分别为6/6/6三环二萜雷公藤甲素的不对称全合成以及6/5/6三环二萜的不对称全合成，提供了全新的合成策略。此外，还申请了两项发明专利，包括鼠尾草酸的高效转化的方法学专利以及抗肿瘤活性二萜衍生物的化合物专利。本项目培养毕业了博士生1名，硕士生1名。