基于自由基加成/碎裂化策略的天然产物合成及其生物作用机制研究

The study of bioactive natural products in term of organic synthesis and chemical biology play a vital role for both the basic research in life sciences and pharmaceutical industry. Galiellalactone and Guanacastepene family of natural products are two attractive chemotypes with promising anti-tumor and anti-microbial activities. Even if their total synthesis have been accomplished via a number of different strategies, a practical route towards these promising natural products that will provide enough materials and diverse analogs has been missing. Based on our careful analysis of their structure features, a novel and general strategy based on the radical cyclization followed by cyclopropane or cyclobutane fragmentation is envisioned, which will provide both natural products in a modular and efficient manner. Starting from readily available strained bicyclic synthons, this synthetic strategy will enable the preparation of various densely functionalized polycyclic systems with high chemo-, regio- and stereoselectivity. Our routes will also be used to prepare specific small-molecule probes for proteomics profiling to provide the potential targets of Galiellalactone and Guanacastepene family of natural products, based on which further chemical biology studies will be carried out to elucidate the mechanism-of-action of these intriguing natural products.

具有生物活性的天然产物，在生命科学基础研究和医学药物领域有着广泛应用，一直以来都是有机合成和化学生物学领域的研究热点。Galiellalactone和Guanacastepene家族天然产物作为两个典型代表，虽然其全合成已经实现，但现有的合成路线难以提供足够量的天然产物样品以及结构类似物进行相关化学生物学研究。本研究中，从简单的张力双环底物出发，我们设计了新颖的自由基关环/小环碎裂化的串联反应策略用于立体选择性地构建关键中间体，进而高效地完成这两个家族天然产物及其类似物的合成，以方便其构效关系的研究。进一步地利用所发展的高效、模块化的合成路线，将于分子中合适的位点引入生物正交的端炔小分子探针。我们将基于二者Michael受体的特性，通过生物大分子质谱的蛋白质组学技术系统性地寻找与小分子探针结合的靶标蛋，为进行小分子作用机制的研究奠定基础。

小分子天然产物是化学生物学研究的重要工具以及药物研发的重要来源。一些具有α,β-不饱和双键的天然产物，能选择性与某些蛋白质的氨基酸残基（如巯基或氨基）进行Michael加成反应，该共价连接使得抑制活性得以大大提高、作用时间也得以显著延长，可期具有良好的药用前景。针对一系列含有Michael受体的复杂天然产物分子，本项目围绕着张力三元、四元环系，设计了新颖的自由基关环/小环碎裂化的串联反应策略用于立体选择性地构建合成中的关键中间体。在化学合成与研究过程中根据实验情况及时调整了研究思路，实现了包括：1）对Galiellalactone的作用机制和靶点蛋白更系统、深入的理解；2）首次完成(−)-Hibiscone C的不对称全合成、高氧化态对映-贝壳杉烷二萜Maoecrystal P和Oridonin的全合成；3）麦角类生物碱的全合成；4）Guanacastepene的全合成探索；5）独角金内酯受体抑制剂的发展等研究。