基于β分泌酶靶点的天然产物Asperterpene A的全合成及其构效关系研究

β-Secretase1（BACE 1）is a rate-limiting enzyme capable of hydrolyzing β-amyloid precursor protein to amyloid peptides (Aβ), and has been considered to be an attractive therapeutic target for the treatment of Alzheimer’s disease. Asperterpene A is a meroterpenoid with unprecedented carbon skeletons, comprising 6 chiral centers. Asperterpenes A and B displayed significant inhibitory activity against BACE 1 in vitro. However, there is no report on total synthesis of asperterpenes. Synthesis of Asperterpenes A and B has been designed with α-arylation of α-substituted ketone and alkylative dearomatization reaction as key steps. Preliminary structure-activity relationship (SAR) against β-secretase 1 will be established via bioassay. This project may not only accomplish the first total synthesis of natural compounds Asperterpenes A and B, obtain SAR against β-secretase 1, but also identify drug candidate targeting β-secretase 1, and elucidate more information about the target structure for designing and synthesis of drugs to selectively inhibit β-secretase 1.

β分泌酶1（BACE1）是生成β-淀粉样蛋白的限速酶，是干扰阿尔茨海默病进程的重要靶点。天然产物Asperterpenes A是一类含有6个手性中心的独特碳骨架的萜类化合物，Asperterpene A和Asperterpene B 对BACE1酶有强的抑制活性，其全合成工作尚未有报道。本项目拟采用不对称α甲基酮的α芳基化及烷基化去芳构化反应（alkylative dearomatization）为关键步骤的合成路线，开展Asperterpene A和Asperterpene B的全合成研究；并在全合成的基础上，合成多个系列骨架修饰的Asperterpene A类似物，初步获得构效关系。本项目不仅有望完成Asperterpene A和Asperterpene B的首次全合成，为Asperterpenes类化合物的全合成提供策略，还有望获得一个结构简单、活性高的BACE 1酶抑制剂候选药物。

天然产物Asperterpenes A是一类含有6个手性中心的独特碳骨架的萜类化合物，Asperterpene A 对BACE1酶有强的抑制活性。本项目拟采用不对称α甲基酮的α芳基化及烷基化去芳构化反应为关键步骤的合成路线，开展Asperterpene A和全合成研究，该项目的后续合成工作将继续进行。与此同时，发展了烯烃的硫硼化反应；发展了单质碘催化喹啉类化合物的还原高效构建四氢喹啉类化合物的方法，并将其应用于药物及天然产物的合成；发展了联烯的氯硼化反应，为２-硅基烯丙基硼化合物的合成提供一种高效的方法；发展了联烯的硼胺化反应，能够直接构建烯基硼取代的含氮杂环化合物；发展了联烯的磷胺化反应，构建了一系列的烯基膦取代的含氮杂环化合物；发展了一种构建联烯基膦化合物的方法。