Salacia属锍糖型具有降糖活性天然产物的全合成、结构修饰及生物活性研究

项目名称： Salacia属锍糖型具有降糖活性天然产物的全合成、结构修饰及生物活性研究

项目编号： No.81473081

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 吴晓明

作者单位： 中国药科大学

项目金额： 75万元

中文摘要： 近年来，从Salacia属植物的根茎部提取的系列具有alpha-葡萄糖苷酶抑制活性锍糖类天然产物小分子以其独特的化学结构和优良的生物活性，受到了人们普遍的关注。体外活性测试表明，该类化合物对alpha-葡萄糖苷酶的抑制活性不亚于已经成功上市的同类药物。因此它们有望作为一类全新的alpha-葡萄糖苷酶抑制剂先导化合物并由此发展成一类全新的降糖药物。本项目将在我们之前对该类天然产物全合成及构效关系大量的研究基础之上：优化这类天然产物中结构最复杂而生物活性最优异的neokotalanol的全合成路线；对天然产物neokotalanol、neoponkoranol及其类似物进行结构修饰，希望获得更高抑制活性的分子作为先导化合物，为进一步的药学研究奠定基础；对上述构效关系研究过程中合成路线中的副反应做进一步反应机理的探讨，并发展相关的糖化学合成方法，希望能够为相关天然产物的合成提供理论基础。

中文关键词： 五层龙；构效关系；结构修饰；生物活性；alpha-葡萄糖苷酶抑制剂

英文摘要： Recently, more and more attention has been drawn on a series of potent alpha-glucosidase inhibitors isolated from Salacia genus plant, which have traditionally been used for the treatment of diabetes in Sri Lanka and the south region of India. Their inhibitory activities against maltase, sucrase and isomaltase known as alpha-glucosidases were revealed to be as potent as those of clinically used alpha-glucosidases inhibitory anti-diabetics. In addition, the chemical structures of these compounds were found quite unique, bearing specific thiosugar sulfonium moiety, which is believed to mimic the oxacarbenium ion-like transition state of the enzyme-catalyzed hydrolysis of carbohydrates. Thus, this group of small molecules has the potential to become a new type of lead compounds as alpha-glucosidase inhibitors, which could be further developed to a new category of anti-diabetics. Based on our previous research of total synthesis and structure-activity relationship (SAR) studies on this group of sulfonium salts, this proposal describes:1) newly designed and more economic strategies to synthesize the most potent inhibitor neokotalanol, the structure of which is the most complicated one among this group of natural products; 2) structure modification on side chain moiety of natural products neoponkoranol, neokotalanol and their five carbon side chain analogs; 3) biological evaluations of the synthesized compounds to discover much more potent alpha-glucosidase inhibitors; 4) development of new synthetic method in sugar chemistry which is based on the investigation of side reaction mechanism of the key reaction to synthesize the above natural products.

英文关键词： Salacia;structure activity relationship;structure modification;biological activity study;alpha-glucosidase inhibitor