喜树碱类肝靶向衍生物的设计合成及其肝靶向机制

项目名称： 喜树碱类肝靶向衍生物的设计合成及其肝靶向机制

项目编号： No.31270397

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 李庆勇

作者单位： 东北林业大学

项目金额： 68万元

中文摘要： 喜树碱是重要的具有抗肿瘤活性的天然产物，对肝肿瘤细胞的体外抑制活性很好，但在体内治疗肝癌效果差和毒副作用大，主要原因是肝靶向差，项目选择生物体内源性的肝靶向物质胆酸及其类似物作为靶向配基，与喜树碱进行偶联，设计合成一系列喜树碱-胆酸偶合物，并通过分子生物学手段对偶合物进行拓扑异构酶抑制活性的评价，考察喜树碱衍生物经过胆酸修饰后是否保持了原有的抗肿瘤作用靶点拓扑异构酶；同时通过胆酸受体表达阳性和阴性的肿瘤细胞进行竞争性平行实验，揭示新偶合物的抗肿瘤效果以及胆酸作为靶标的分子机制，利用分子手段考察新偶合物作用后的肿瘤细胞中喜树碱诱导调亡的特征调亡蛋白量和胆酸诱导的蛋白量的变化，进一步揭示新衍生物的肝靶向机制；通过动物体内代谢和组织分布等实验进一步验证新偶合物的肝靶向性。该项目实施将为肝靶向性的喜树碱衍生物的设计合成提供新思路，为胆酸作为肝靶向物质的靶标提实践依据，并揭示其作为肝靶标的分子机制

中文关键词： 喜树碱；胆酸；前药设计；肝靶向；抗肿瘤

英文摘要： Camptothecin is an important natural product with anti-tumor activity，which show good inhibitory activity against liver tumor cells in vitro , but show the bad effect of treatment of liver cancer in vivo and toxic side effects mainly due to poor liver targeting. In this project, Bile acid and its analogues are selected as targeting ligands because of its own biological bodyderived liver targeting substances , and a series of camptothecin-bile acid conjugates are designed and synthesized. The topoisomerase inhibitory activity of these conjugates are evaluated to examine the original anti-tumor targets topoisomerase of camptothecin derivatives after a bile acid modification; The antitumor targeting effect of these conjugates are checked by competitive parallel experiment using the bile acid receptor expression of positive and negative tumor cells, and bile acid molecular mechanisms as targets are investigated. Molecular techniques are using to examine the characteristics of apoptosis protein induced by bile acid and camptothecin and protein changes induced by the new conjugates in liver cancer cells; The new conjugates of liver targeting metabolism in vivo and tissue distribution experiments are performed.The liver targeting camptothecin derivatives are designed and synthesized to provide new ideas for targeting

英文关键词： camptothecin；cholic acid；prodrug design；targeting；antitumor