对映-贝壳杉烷类二萜的全合成、结构多样性制备及抗肿瘤活性的研究

Screening natural products and their analogs is an important way of discovering antitumor drugs. The ent-kaurane diterpenoids are one class of natural products that show significant antitumor activity. This study focus on constructing a molecular library conveniently and seeking for candidate molecules with further research and clinical value by taken advantage of total synthesis combined with the modification and derivation of privileged structures of this class of diterpenoids. The strategy featuring constructing the tetracyclic molecular skeleton of diterpenoids first, then functionalizing and oxidizing molecular skeleton in late-stage is adopted in synthesis route, which starting from the commercially available Wieland-Miescher ketone. This total synthesis is designed to construct a molecular library, not just synthesis one specific molecule by simplified the skeletal structure, adjusted the molecular chiral center and oxidized different sites in the skeleton. On this basis, in vitro and in vivo antitumor activity of this molecular library is evaluated which lays the foundation for the development of a new class of antitumor drug candidates.

从天然产物及类似物中筛选活性分子是目前研发抗肿瘤药物的重要途径。对映-贝壳杉烷类二萜是一类具有显著的抗肿瘤活性的天然产物。本项目拟利用天然产物全合成的手段，通过与该类二萜优势结构的修饰、衍生相结合，简洁高效的构建结构多样的分子库，寻找有进一步研究和临床价值的候选分子。全合成采用先构建分子的四环二萜骨架，后对分子骨架进行官能团化、氧化的合成策略，以简单可规模化制备的Wieland-Miescher酮作为起始原料；在后期阶段的官能团化、氧化中，不以某个具体的天然产物为合成目标，而是合成工作与二萜稠环结构的简化、分子手性中心的调整、骨架中不同位点的氧化等结构修饰相结合，对该类二萜进行结构多样性制备。在此基础上对所合成的分子库进行体外抗肿瘤活性评价、作用机制研究及体内动物试验，为研发新一类抗肿瘤候选药物奠定基础。

天然产物及类似物的高效合成与活性筛选是研发抗肿瘤药物的重要途径。对映-贝壳杉烷类二萜是一类具有显著的抗肿瘤活性的天然产物。利用仿生、发散性合成策略，高效完成四类二萜骨架（贝壳杉烷型、绰齐烷型、贝叶烷型和阿替生烷型），两类杂萜骨架（guignardone和manginoid）和两类倍半萜性（norascyronone和eudesmol）的搭建，以及12个相关天然产物的全合成工作，同时对贝壳杉烷型二萜抗肿瘤机制进行了初步探讨。相关成果发表在Angew Chem Int Ed Engl（2篇）和Org. Lett （1篇）杂志