大花旋覆花内酯抗肿瘤衍生物合成、构效关系和作用机制研究

项目名称： 大花旋覆花内酯抗肿瘤衍生物合成、构效关系和作用机制研究

项目编号： No.31200254

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 微生物学、植物学

项目作者： 汤江江

作者单位： 西北农林科技大学

项目金额： 22万元

中文摘要： 天然活性物质在医药和农业等领域具有重要的地位。对天然活性化合物作进一步的结构改造或修饰，使其成为更高活性的先导药物，是当今新药创制的主要途径之一。 1-O-乙酰基大花旋覆花内酯(ABL)是菊科旋覆花属植物中一个具有抗肿瘤药理活性的倍半萜类天然产物。前期细胞毒活性结果表明，ABL对三株人癌细胞（NCI H460、HeLa和HepG2）增殖具有中等抑制活性。本项目以ABL为先导化合物，分别从1-位乙酰基，6-位羟基和13-位环外双键三个位置进行结构修饰，通过酰基化、亲核加成和Heck偶联等反应半合成一系列衍生物，运用现代波谱等技术对其结构进行归属和表征，借助细胞毒活性筛选实验分析其构效关系，以期发现活性高、毒性低的新先导化合物，进而采用细胞凋亡和细胞周期干预等实验探讨高活性化合物的抗肿瘤作用机制，为新型抗肿瘤药物研究提供化学和药理学基础数据和理论依据。

中文关键词： 大花旋覆花内酯；先导化合物；构效关系；抗肿瘤；

英文摘要： Natural active products play a highly significant role in the development of many areas including medicine and agriculture. To obtain higher active lead drugs, structural modification of natural active compounds is now still one of the main ways in the drug discovery and development process. 1-O-acetylbritannilactone (ABL) isolated from compositae Inula species is a sesquiterpene lactone. We found that ABL has high content in Inula britannica, and had shown moderate antitumor activities against NCI H460, HeLa and HepG2 cells. In this subject, several series of derivatives with ABL as the lead compound will be designed and semisynthesized on the 1-acetyl, 6-hydroxyl and 13-exocyclic double bond of ABL by acylation, nucleophilic addition and Heck coupling reactions, respectively. In addition, the structure of ABL derivatives will be elucidated by modern spectral analysis, and their antitumor activities will be investigated through cytotoxic activity screening, and their structure-activity relationships (SAR) will be analyzed, so as to find new lead compounds with high activity and low toxicity. Moreover, the primary antitumor mechanisms will be also discussed using molecular biology techniques including apoptosis and cell cycle assays. These data will provide theoretical and experimental evidences of chemistry and

英文关键词： britannilactone；lead compounds；structure-activity relationship；antitumor；