系列C20差向异构ocotillol型皂苷的合成、心肌缺血/再灌注损伤保护作用构效关系、ADME与作用机制研究

项目名称： 系列C20差向异构ocotillol型皂苷的合成、心肌缺血/再灌注损伤保护作用构效关系、ADME与作用机制研究

项目编号： No.81473104

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： 孟庆国

作者单位： 烟台大学

项目金额： 65万元

中文摘要： 现有研究表明，人参皂苷具有广泛的心肌保护作用，我们前期研究发现，系列(20S,24R)-ocotillol型皂苷对心肌缺血损伤的保护作用明显优于其C24差向异构体，吸收与代谢亦存在显著立体差异。本项目基于前期研究基础，设计合成12对C20差向异构ocotillol型皂苷，采用NMR、HRMS和X-ray单晶衍射表征其结构；建立基于体外心肌线粒体和心肌细胞缺氧/复氧模型以及基于离体器官和整体动物的心肌缺血/再灌注损伤模型，研究其对体内外心肌缺血/再灌注损伤保护作用的构效关系，明确其对心肌缺血/再灌注损伤的保护作用机制与改善氧化胁迫状态、保护线粒体稳态的相关性。针对活性存在显著差异的C20差向异构体，研究其ADME的立体差异及其发生机制，进一步阐明C20差向异构ocotillol型皂苷活性差异与ADME的关联性。为阐释人参的经典功效和开发具有独立知识产权的抗心肌缺血新药提供新策略和科学依据。

中文关键词： C20差向异构ocotillol型皂苷；合成；构效关系；心脏缺血/再灌注损伤；ADME

英文摘要： It has been shown that ginsenosides have widely beneficial myocardial protective effects. Our previous study results show that protective effects of series (20S, 24R)-ocotillol-type sapanions on myocardial ischemia injury are more significant than those of their associated C24 epimers. Their absorption and metabolism also have stereoselective differences. Based on our previous experiment results, twelve pairs of C20 epimeric ocotillol-type sapanions have been designed and to be synthesized in this study. Their structures are characterized by NMR, HRMS and X-ray single-crystal diffraction. The hypoxia/reoxygenation model based on in vitro cardiac muscle mitochondria and cardiomyocyte and the myocardial ischemia/reperfusion injury model based on vivi animal have been established. Their structure-activity relationships(SAR) of in vivo-in vitro myocardial ischemia/reperfusion injury protective effects will be studied. The relevance of their myocardial ischemia/reperfusion injury protection mechanism with oxidative stress state improvement and mitochondrion steady state protection will be elucidated. In order to further elucidate the correlathion between activities and ADME of C20 epimeric ocotillol-type sapanions, the stereoselective differences of ADME and occurrence mechanism of those C20 epimers which have significant different activites will be studied. Novel strategies and scientific evidences can be provided to elucidate the classic efficiency of Panax Ginseng and enhance R&D of novel myocardial anti-ischemia drug with independent intellectual property.

英文关键词： C20 epimeric ocotillol-type sapanions;synthesis;SAR;myocardial ischemia/reperfusion injury;ADME