楝属植物中高选择性11β-HSD抑制剂的发现及其抗糖尿病活性研究

The over-expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) is closely related to the insulin resistance of diabetes patients.The feasibility to find lead compound from triterpenoids to treat diabetes is proved by glycyrrhetinic acid, which shows significant inhibitory activity but poor selectivity against 11β-HSD. The total triterpenoids of Melia genus plants from Yunnan and Guangxi showed significant hypoglycemic activity.The applicant isolated series of triterpenoids from Melia azedarach collected in Yunnan, among which two of them showed significant inhibitory activities against 11β-HSD of human with high selectivity. This project is planned to investigate the chemical constituents of two species of Melia genus medicinal plants yielded in Guangxi mainly by chromatography and spectrum analysis methods, and to screen inhibitory activities in vitro of the isolated triterpenoids against 11β-HSD by scintillation proximity assay, and finally to evaluate the inhibitory activities and pharmacodynamics in vivo of these compounds in diabetes rats induced by uninephrectomy combined with high-fat feed diet. The purpose of this project is to find new and excellent inhibitors with high selectivity against diabetes from the selected plants. It is of great importance to achieve lead compounds with good prospect to cure diabetes and to explore ethnomedicinal plants resources reasonably.

11β-羟基类固醇脱氢酶（11β-HSD）的过量表达与糖尿病患者的胰岛素抵抗密切相关；三萜化合物甘草次酸能显著抑制11β-HSD的活性，为从三萜类成分中发现治疗糖尿病先导化合物提供了可行性，但其选择性差。活性预试表明，云南和广西产楝属植物总三萜部位均具有明显的降糖活性，申请者前期已从云南产苦楝活性部位分离得到系列三萜类化合物，其中2个三萜能显著抑制人11β-HSD的活性并具有良好的选择性。本项目拟在前期研究的基础上，主要采用色谱法和波谱法对广西产楝属植物的活性部位进行化学成分研究，通过液闪接近测定技术完成所得化学成分的体外抑制11β-HSD活性和选择性评价，并采用单侧肾切除手术联合高糖高脂饮食诱导的糖尿病大鼠作为动物模型进行体内活性和药效学评价，以期发现结构新颖并具有良好体内活性的高选择性11β-HSD抑制剂。该项目对治疗糖尿病活性先导化合物的发现和特色植物资源的合理开发利用具有重要意义。

糖尿病已成为我国主要的公共健康问题之一，其发病原因复杂，多种酶的活性表达均与糖尿病的发生发展密切相关。. 本项目旨在通过系统研究两种云南和广西产楝属植物的化学成分，完成其活性筛选、构效关系分析研究，以期寻找抗糖尿病候选分子。通过本项目的实施，从苦楝(Melia azedarach)和川楝(M. toosendan)中共分离得到81个化合物，涵盖了三萜类（含降三萜）、甾醇类、黄酮等骨架类型，其中新化合物12个。完成部分化合物体外11β-HSD、DPPIV抑制活性和GK、SIRT1激动活性的筛选，研究结果表明，云南产和广西产苦楝在化学成分类型上没有明显差异，均以甘遂烷型三萜和孕甾烷型甾体为主；2个化合物对人11β-HSD1具有显著的抑制作用并对11β-HSD2良好的选择性，可作为抗糖尿病药物深入研究的候选分子。已发表研究论文3篇，SCI收录期刊已接收1篇，培养硕士研究生2人，所指导本科生作品获得国家级比赛二等奖1项，省级三等奖1项。上述研究进展已基本实现了任务书的预期目标。