MPC1001生物碱的不对称合成、修饰与抗肿瘤活性评价

抗肿瘤药物的研发是一项长期且富有挑战性的工作。活性天然产物极其丰富的结构多样性和瞩目的生物学活性能够为先导化合物筛选，新靶点和作用模式的发现不断提供启发和思路。MPC1001是含有独特双硫代二酮哌嗪骨架和十五元大环内酯结构的复杂生物碱，具有非常显著的抗肿瘤（如前列腺癌，早幼粒细胞白血病），抗病毒和潜在抗结核活性，是全合成领域里的明星分子。本项目以MPC1001与MPC1001C为目标分子，采取汇聚式合成策略进行高效的化学全合成。合成路线创造性地采用氟离子介导的内酯开环与关环复分解联用的策略构建二氢氧杂卓骨架和钯催化的插羰酯化反应合成大环内酯。在全合成基础上，通过多角度的结构修饰，对MPC1001进行结构改造与简化，实现衍生物的制备与构效关系的研究。以体外抗肿瘤活性测试数据为指导，发现潜在高效的先导化合物，为今后深入研究作用靶点，开发新的抗肿瘤药物奠定基础。

The discovery of new anti-tumor drugs is a long-term and challenging task and natural products inspire the exploration of new drug targets and mechanisms with tremendous structural diversity and impressive bioactivities. MPC1001 is a star molecule containing an unusual epidithiodiketopiperazine core and a 15-membered macrolactone that shows multi-activities such as anti-tumor (e.g. prostate cancer, promyelotic leukemia), anti-virus and ant-ituberculous. This project aims to establish a scalable total synthesis of MPC1001 and MPC1001C through a highly efficient pathway. Key strategies such as fluoride mediated lactone ring-opening and ring-closing metathesis to dihydrooxepine skeleton and palladium catalysed carbonylation to macrolactone motif will be introduced. Moreover, structural manipulation and simplification on MPC1001 will be carried out to investigate the structure-activity relationship. Through the in vitro anti-tumor activities evaluation of all analogues, the proper lead compound will be screened to facilitate the anti-tumor drug discovery in the future.