新骨架萘醌杂萜三七放线菌素的不对称全合成与免疫抑制活性评价

Naphthoquinone meroterpenoids are hybrid natural products of both polyketide and terpenoid origin. Sanqimycins，a new type of naphthoquinone meroterpenoids，have been isolated from endophytic Streptomyces sp. and found to exhibit immunosuppressive activity. They are a group of hybrid sesquiterpene–polyketide natural products with novel carbon skeleton containing three fused six-membered rings in the sesquiterpene part. In this project, sanqimycins are selected as targets for our synthesis design, wherein how to effectively construct the fused-ring skeleton constitutes a synthetically challenging issue. In view of this, an ingenious one-step biomimetic cyclization could be designed for expeditious assembly of the novel carbon skeleton, which will give quick synthetic access to the chiral sanqimycins. On the basis of this, the absolute configuration of the natural products could be assigned. Then, a directional strategy for the diversity-oriented synthesis could be used to modify the molecular structures and prepare sanqimycin analogues with diverse structures for further evaluation of immunosuppressive activity. The present studies could not only provide reference for total synthesis of naphthoquinone meroterpenoids with unique structure from the perspective of strategy and methodology development, but also lay the foundation for the study on immunosuppressive activity of these compounds and offer possibility for chemical biology research on related molecules from the perspective of molecular function investigation.

萘醌杂萜属于聚酮单元和萜杂合的一类天然产物。三七放线菌素（Sanqimycins）是从三七植物内生放线菌 Streptomyces sp. 中发现的具有免疫抑制活性的新骨架萘醌杂萜。它们是倍半萜与聚酮的杂合体，其中倍半萜部分由三个六元碳环稠合而成，结构新颖且复杂。本项目以 Sanqimycins 为研究对象，针对其稠环体系的构建问题设计了一步巧妙的仿生环化反应，并最终完成其不对称全合成，进而确认天然产物的绝对构型。然后采用结构多样性导向的合成策略，对化合物的分子结构进行改造和修饰，合成结构多样的三七放线菌素衍生物，用于进一步的免疫抑制活性评价。因此，开展三七放线菌素及其类似物的全合成研究不仅可以从策略和方法发展的角度为该类结构独特的萘醌杂萜类化合物的化学合成提供借鉴和参考，而且还可以从分子功能探讨的角度为该类化合物的免疫抑制活性研究奠定物质基础，并为后续相关分子的化学生物学研究提供可能。

三七放线菌素类天然产物是一类具有免疫抑制活性的新骨架萘醌杂萜类天然产物，由III型聚酮与倍半萜杂合而成，其倍半萜部分是三个六元环组成的稠环体系，在已知的天然产物中尚未有该类骨架报道。本项目基于可能的生物合成途径，在探索合成倍半萜rac-2的基础上，通过倍半萜与flaviolin衍生物的缩合反应制备了三七放线菌素的关键中间体，而该类化合物中复杂的稠环结构则通过该中间体经一步仿生环化反应得到。虽然没有完成目标天然产物的全合成研究，但是经过我们长期的合成探究，已实现两个三七放线菌素类化合物的消旋全合成，为该类化合物的首次合成，并通过关键中间体的X-Ray单晶衍射确定了三七放线菌素的相对构型。此外，手性合成和多样性合成工作也已开展，将进一步确定三七放线菌素的绝对构型，并提供一批化合物用于免疫抑制活性测试。