杉科植物中松香烷型二萜抗动脉粥样硬化活性的发现及构效关系研究

项目名称： 杉科植物中松香烷型二萜抗动脉粥样硬化活性的发现及构效关系研究

项目编号： No.81473112

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： 姚胜

作者单位： 中国科学院上海药物研究所

项目金额： 70万元

中文摘要： 降血脂是针对动脉粥样硬化最有效的治疗手段。在天然产物体外降脂活性筛选中，我们首次发现杉科植物中的松香烷型二萜具有明显的降血脂活性，并通过动物实验证实了LSP-6-6的体内药效。初步研究表明LSP-6-6的降血脂活性与LDLR上调相关。在此基础上，本项目拟系统评价杉科植物中LSP-6-6天然衍生物的降血脂活性，深入研究LSP-6-6的降血脂作用机制，初步总结构效关系；通过化学沟通和全合成的方法，合成含不同官能团的LSP-6-6衍生物，解决活性天然产物资源限制；通过对LSP-6-6的结构改造与修饰，系统考察A、B、C环及环上取代基的变化、以及C-18、C-20位甲基的变化对降血脂活性的影响，以期通过系统的构效关系研究能够发现生物利用度高、活性好、安全性高的抗动脉粥样硬化的先导化合物，为从松香烷型二萜中开发出具有自主知识产权、结构新颖和作用机制明确的抗动脉粥样硬化的一类新药提供科学依据。

中文关键词： 松香烷型二萜；抗动脉粥样硬化；结构改造；构效关系

英文摘要： Lowering cholesterol levels in blood is the best effective treatment for atherosclerosis. In pursuing of the anti-hyperlipidemic constituents from natural products, it is the first time for us to find that abietane diterpenoids from Taxodiaceae family are significant effective to increase the uptake of blood cholesterol levels by HepG2 cell in vitro. Further investigation revealed that abietane diterpene named LSP-6-6 remarkably decreased the level of total cholesterol, total glycerides and LDL in the blood of high-fat fed golden hamster. Preliminary mechanism study suggested the anti-hyperlipidemic activity of LSP-6-6 was closely related to the up-regulation of LDLR level in cell. To explore the anti-atherosclerosis mechanism of abietane diterpenoids and structure-activity relationship (SAR), natural LSP-6-6 derivatives from Taxodiaceae family will be fully evaluated by HepG2 uptake assay and preliminary SAR will be concluded on the basis of screening results. The anti-hyperlipidemic mechanism of LSP-6-6 will be performed in-depth to check the changes of the lowering cholesterol targets inclduing HMGCoA,PSCK9, CEPT, CYP7A1 and ACAT in gene and protein level. Additionally, LSP-6-6 derivatives with functional groups at different sites of the skeleton, such as hydroxyl at C-3 and carboxyl at C-18 or C-20, will be synthesized to break through the limitation of natural products by using 2, 2-dimethyl-1, 3-cyclohexanedione, abietic acid and carnosic acid as starting materials, respectively. Consequently, modification of LSP-6-6 focused on functional groups will be carried out for systematic evaluation of structure-activity relationship of abietane diterpenoids. We expect that lead compounds with pretty bioavailability, high efficacy and low toxicity will be generated from SAR research and our study will supply scientific foundation for the development of anti-atherosclerosis drugs from abietane diterpenoids.

英文关键词： abietane diterpenoids;antiatherosclerotic;structural modification;structure-activity relationship