新型抗生素Amycolamicin的全合成和构效关系研究

Complex glycoconjugate amycolamicin, a natural antibiotic isolated from soil bacteria, has a novel structural skeleton and displays broad-spectrum inhibition against various bacteria. Moreover, it can effectively kill multiple types of superbacteria, which makes it highly worthy of study since bacterial drug resistant has become a serious growing threat globally. On the other hand, its chemical synthesis is a challenge to modern organic chemistry due to its complex structure, and there is no synthetic report as far as we know. In this project, we will adopt the mild Au(I)-catalyzed glycosylation, which was developed by our group recently, to address the pivotal glycosylation coupling. The synthesis of amycolamicin will be accomplished via a concise and efficient modular route, based on which a series of analogues will also be synthesized. Then we will examine their bioactivities, and the resulting structure-activity relationship should serve the further drug development.

复杂糖缀化合物amycolamicin是一种从土壤细菌中分离得到的天然抗生素，拥有新颖的结构骨架。它不仅对细菌具有广谱的抑制活性，而且能够有效杀灭多种超级细菌，是解决目前细菌抗药性日益严重问题的极有潜力的药物研究对象。Amycolamicin复杂的分子结构对现代化学合成也是一个挑战，目前尚未有合成报道。本项目将应用本课题组发展的新型一价金催化糖苷化来解决其中关键的糖苷化问题，力求通过一条简洁高效的模块式合成路线来完成amycolamicin的全合成；并在此基础上进行类似物的合成和活性测试，获得有价值的构效关系，为药物开发打下基础。

复杂糖缀化合物Amycolamicin是一种从土壤细菌中分离得到的天然抗生素，拥有新颖的结构骨架。它不仅对细菌具有广谱的抑制活性，而且能够有效杀灭多种超级细菌，是解决目前细菌抗药性日益严重问题的极有潜力的药物研究对象。本项目以L-岩藻糖和L-缬氨酸甲酯作为基础原料，利用俞氏糖苷化方法，立体选择性合成了L-Amykitanose连接Tetramic acid的结构片段；接着从α葡萄糖甲苷出发合成了D-Amycolose片段；之后从简单易得的山梨酸和四氢呋喃出发合成了反式十氢化萘结构片段；最后通过俞氏糖苷化和缩合反应，完成天然产物Amycolamicin的全合成。除此之外，我们还得到一系列Amycolamicin合成中的结构片段，以及天然产物分子的三个立体异构体。接下来，我们将对合成的样品和中间体进行生物活性测试，研究其抗菌作用机理。同时，通过构效关系研究，探索结构简单、活性更优的类似物。