新型α-葡萄糖苷酶抑制剂呫吨衍生物的结构优化与协同作用

项目名称： 新型α-葡萄糖苷酶抑制剂呫吨衍生物的结构优化与协同作用

项目编号： No.21272290

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 汪波

作者单位： 中山大学

项目金额： 80万元

中文摘要： α-葡萄糖苷酶抑制剂因可以调控糖代谢和糖蛋白、糖脂的合成而可能成为治疗II型糖尿病的药物以及抗肿瘤抗病毒药物，因此其研究备受关注。近年来国内外研究已经发现呫吨酮衍生物具有良好的α-葡萄糖苷酶抑制活性。在前期研究中，我们已经获得了较明确的构效关系，初步阐明了其作用机制，并发现了呫吨酮衍生物之间的协同作用。在此基础上，本申请课题拟运用合理药物设计原理设计合成（1）呫吨酮与多种糖以不同方式或不同构型的鍵合衍生物和（2）芳杂环取代的呫吨酮衍生物或类似物等两类结构优化的呫吨酮衍生物，深入研究各衍生物对α-葡萄糖苷酶的抑制活性、构效关系以及作用机制；系统研究各呫吨酮衍生物之间的协同作用，并在此基础上合成多种鍵合方式连接的双呫吨酮衍生物。期望发现新的高活性的α-葡萄糖苷酶抑制剂或组合，并阐明这些抑制剂与酶的相互作用。

中文关键词： α-葡萄糖苷酶抑制剂；呫吨酮衍生物；协同作用；构效关系；结构优化

英文摘要： α-Glucosidase inhibitors are involved in the digesting of carbohydrates and the processing of glucoproteins and glycolipids, and hence may serve as new therapeutic agents for some closely related modern diseases, such as diabetes, HIV and cancer. In recent years, xanthone derivatives have been found to be a class of potent α-glucosidase inhibitors. In previous studies we have obtained some useful insight into the structure-activity relationships of a series of synthesized xanthone derivatives and their inhibition mechanism. Based on these findings and the principle of rational drug design, we propose the design and synthesis of a library of structurally optimized xanthone derivatives, with the aim to discover novel and potent α-glucosidase inhibitors and to clarify the inhibition mechanism. These derivatives include (1) monosaccharide-xanthone conjugates tethered in diverse manners and configurations, and (2) heterocycle-containing xanthone derivatives and analogs. In addition, we propose to perform systematic studies of the synergetic inhibition between xanhone derivatives of different types, and subsequently to synthesize a family of dimeric xanthone derivatives linked with varying spacers. We expect to develop some novel and potent α-glucosidase inhibitors or combinations for practical application, along with

英文关键词： α-Glucosidase inhibitors；Xanthone derivatives；Synergetic Effect；Structure-Activity Relationship；Structural optimization