具有抗肿瘤活性的姜科二萜构效关系研究

项目名称： 具有抗肿瘤活性的姜科二萜构效关系研究

项目编号： No.81460533

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 赵庆

作者单位： 云南中医药大学

项目金额： 43万元

中文摘要： 天然产物的结构优化及定量构效关系研究，是发现新药的一个重要渠道。从天然产物及其衍生物中寻找抗肿瘤活性成分或先导化合物，是抗肿瘤药物研究与开发的一个重要方向。我们的前期研究结果和文献报道表明：通过结构改造得到的丁烯酸内酯型二萜和姜科植物中的该类型二萜，大多数对多种肿瘤细胞具有显著的细胞毒或抗肿瘤活性，该类二萜的活性强弱与分子中B环的取代基、C-11(12)位的反式烯键有很大关系。本项目拟以两种姜科植物中的呋喃二萜为原料，制备系列丁烯酸内酯型二萜衍生物，特别是C-6β位有酰氧基取代的衍生物，采用五种肿瘤细胞株对所合成的衍生物进行细胞毒活性测试，并选择2-3个活性较好的衍生物进行小鼠体内抗肿瘤活性评价。同时采用3D-QSAR，对丁烯酸内酯型二萜的结构与细胞毒活性的关系进行分析，进一步指导该类二萜衍生物的结构优化，系统评价该类二萜成分的细胞毒活性，为发现活性更强的分子或先导物提供科学依据。

中文关键词： 三维定量构效关系；抗肿瘤活性；二萜；姜科；结构优化

英文摘要： Structure optimization of natural products, and studies on quantitative structure-activity relationship of them, is an important pathway of finding new medicines. Searching for antitumor components or lead compounds from natural products or their analogues, is an important direction of research and development of antitumor medicine. In our previous researches and those reported in the literature, a lot of butenolide diterpenes isolated from Zingiberaceae plants or obtained from structure transformation of the Zingiberaceae diterpenes, showed significant cytotoxic or antitumor activities against several cancer cells. We found that the activities were closely related to the substituent group of B-ring of the molecular, and C-11(12) trans-double bond. This project consists of the following contents: The diterpenes isolated from two kinds of Zingiberaceae plants are subjected to structure transformation reaction to obtain series of butenolide derivatives, especially those containing an acyloxy group at C-6β situation. The butenolide diterpenes are subjected to in vitro cytotoxic bioassays, and two or three of them that showed strong cytotoxic activities, are subjected to in vivo anticancer activity in mice. At the same time, 3D-QSAR is employed to analyze the detailed relationship of cytotoxic activities of the butenolides and their structures, which provides further guidance for subsequent structure optimization of butenolide diterpenes and systematic evaluation of their cytotoxic activities, and provides scientific basis for the discovery of more active molecules or lead compounds.

英文关键词： 3D QSAR;antitumor activity;dietrpene;Zingberaceae;structure optimization