Rubradirin的全合成、类似物化合物库的构建及其抗菌活性研究

Due to the increasing drug resistance to the current antibiotics and lack of new antibiotics with novel mechanisms, bacterial infections have become a threat to human health. Rubradirin was isolated via the fermentation of Streptomyces achromogenes var. rubradiris in 1965. Rubradirin is highly active against a variety of Gram-positive bacteria both in vitro and in vivo, and its activity has been shown to be the consequence of its impairment of ribosomal functions by the selective inhibition of bacterial protein synthesis. It’s effective against multi-drug-resistant stains, and exhibited an ED50 of 125 nM against Methicillin-Resistant Staphylococcus aureus (MRSA). However, due to the scarcity of Rubradirin from nature, further studies on Rubradirin’s mechanism and potential in clinical uses have been limited. Rubradirin has a unique molecular architecture with dense functionalities and compact structure. Its 13-membered fused ring system represents certain strain. Its total synthesis represents a synthetic challenge. No total synthesis on Rubradirin has been reported to date. ..This project aims at the total synthesis and profiling of Rubradirin and its analog library. Our synthetic strategy features the macrocycle formation via the Mitsunobu reaction, and stereoselective intramolecular hydroxy Michael addition to simultaneously construct the morpholine moiety and 13-membered ring system. So far, we have successfully synthesized Rubradirin’s fused core structure in the model system, and propose to continue the studies to complete the total synthesis of Rubradirin and its analog library, as well as their biological profiling. The ultimate goal is to identify more effective yet simplified Rubradirin analogs for pharmaceutical applications.

红迪菌素是1965年从 Streptomyces achromogenes var. rubradiris 发酵液中分离得到的具有显著抗菌活性的天然产物，在体内体外都对革兰氏阳性菌具有明显的抑制作用。红迪菌素很难分离得到，其作用机制和临床应用研究受到局限。其结构新颖，分子稠环核心骨架官能团密集，含有多个手性中心，其13元环系相对刚性。红迪菌素的全合成具有挑战性，尚未见报道。.本项目以红迪菌素的全合成及抗菌活性为研究内容，建立新的合成策略以完成红迪菌素的全合成。合成策略包括（1）分子内Mitsunobu反应形成15元氮杂环；（2）羟基的分子内立体选择性Michael加成反应同时构建吗菲啉和13元环系。通过探索红迪菌素的合成策略，发展一条简便易行的合成路线完成其全合成及类似物化合物库的构建。进一步对红迪菌素及其类似物的活性筛选、构效关系研究、结构优化，寻找具有临床应用前景的先导化合物。

红迪菌素是1965年从 Streptomyces achromogenes var. rubradiris 发酵液中分离得到的具有显著抗菌活性的天然产物，在体内体外都对革兰氏阳性菌具有明显的抑制作用。红迪菌素很难分离得到，其作用机制和临床应用研究受到局限。其结构新颖，分子稠环核心骨架官能团密集，含有多个手性中心，其13元环系相对刚性。红迪菌素的全合成具有挑战性，尚未见报道。. 本项目以红迪菌素的全合成为主要研究内容。发展了一条简便、易行的合成路线，首次完成了天然产物Rubradirin的母核结构；发展了使用铜催化的分子内C-O偶联反应构建红迪菌素ABC环的策略，在同样的条件下，该方法也适用于制备包含天然产物Hygrocin B的萘醌并七元杂环的体系，形成C-C键。偶然发现了通过Zn(OTf)2催化的级联转化反应来构建桥联环萘醌衍生物的方法，并对该方法的适用范围、机制进行了研究。. 该项目的实施，为红迪霉素类天然产物的进一步研究与开发打下坚实的基础。