7-去氮核苷天然产物的全合成及生物活性研究

项目名称： 7-去氮核苷天然产物的全合成及生物活性研究

项目编号： No.21462019

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 无机化学

项目作者： 肖强

作者单位： 江西科技师范大学

项目金额： 55万元

中文摘要： 7-去氮嘌呤核苷广泛存在于微生物和海洋动植物中，具有良好的抗菌、抗病毒和抗肿瘤活性，其衍生物作为腺苷激酶抑制剂和抗HCV药物已进入三期临床研究，但迄今为止该类化合物仍缺少有效的合成方法。本项目将解决Vorbrüggen糖基化不适于合成7-去氮嘌呤核苷的方法学难题，系统研究糖基化时碱基的取代基、溶剂、温度和催化剂对反应的影响，最终将Vorbrüggen糖基化应用于该类化合物的合成；本项目还将研究利用流式化学合成仪反应重复性好、无放大效应和便于自动化控制等优势来改善此类化合物的合成；此外，为解决常规核苷合成中使用过量路易斯酸所产生的问题，本项目将探讨使用催化量Br?nsted Acid代替路易斯酸的可行性；最后，利用优化的反应方法完成已知天然7-去氮嘌呤核苷的全合成，形成具有100个结构多样性分子的化合物库，测定其抗肿瘤和抗HCV病毒活性，研究活性与结构的关系，为进一步开发此类药物提供依据。

中文关键词： 有机合成化学；构效关系；生物活性分子合成；杂环化合物；天然产物全合成

英文摘要： 7-deazapurine nucleoside is a component of natural nucleic acids found in microorganisms and marine organisms that have demonstrated exceptional anti-bacterial, anti-infection, anti-viral, and anti-cancer activity. Their derivatives have been tested in clinical phase III trials as an anti-HCV drug and an inhibitor of adenine kinase respectively. This project will focus on solving the challenges that current Vorbrüggen glycosylation reaction condition is not suitable for the synthesis of 7-deazapurine nucleoside. The impact of the structure of the nucleoside, the solvent, the temperature, and the nature and the amount of the catalyst will be systematically studied and optimized reaction conditions will be proposed. Meanwhile we will evaluate whether we can tak advantage of Flow Chemistry equipment to facilitate the synthesis. Also, in order to solve the problems due to the excessive use of lewis acid catalys in traditional nucleoside synthesis, we will investigate the possibility of replacing lewis acid with catalytical amount of Br?nsted-Lowry acid. Ultimately we plan to use the method out of this research to synthesize naturally occurring 7-deazapurine nucleosides reported in the literature and establish a structurally diversified chemical library with about 100 compounds. We will test their activity against HCV and antitumor activities, and use the SAR information attained to guide future study and development of those drugs.

英文关键词： organic synthesis;structure and activities realtionship;molecule with biological activities;heterocylce compounds;total synthesis of natural products