斑蝥素类PP1和PP2A双重抑制剂的结构优化与构效关系研究

项目名称： 斑蝥素类PP1和PP2A双重抑制剂的结构优化与构效关系研究

项目编号： No.81202411

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 邓莉平

作者单位： 绍兴文理学院

项目金额： 23万元

中文摘要： 天然产物的结构优化是新药研发的重要途径之一。本课题以具有抗肿瘤活性并含独特升高白细胞作用的PP1和PP2A蛋白磷酸酶抑制剂-天然产物斑蝥素为研究对象，在总结前期研究成果的基础上，根据PP1和PP2A的结构特点，利用分子杂合、类药性分析等合理药物设计及计算机辅助方法，设计新型斑蝥素衍生物，并在虚筛及初步类药性评价的基础上，定向合成目标分子，分别从细胞和分子水平筛选目标分子的抗肿瘤活性及PP1、PP2A酶抑制作用，分析构效关系，并在动物体内抗肿瘤活性评价的基础上，力争优选出1-2个具有开发前景的新颖抗肿瘤候选药物。

中文关键词： 斑蝥素；抗肿瘤；蛋白磷酸酶；结构优化；构效关系

英文摘要： The structural optimization of the natural products is an important way for new drug development. Cantharidin is the active principle of the Chinese blister beetle (Mylabris phalerata) which exerts profound cytotoxicity towards tumor cells since it has been reported to have an effect on the control of cell cycle regulation, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) inhibitors. This programme, based on the research results of preliminary studies, according to the structural features of PP1 and PP2A，rational drug design and computer assisted analysis to design new types of cantharidin derivtive, and according to virtual screening and evaluation of the initial drugs, to direct the synthesis of target molecules, furthemore, from the cellular and molecular level of screening antitumor activity of the target molecule and PP1 and PP2A inhibitions and analysis of SAR, to strive preferably 1-2 novel antitumor candidate drugs on the basis of in vivo antitumor activity evaluation.

英文关键词： cantharidin；antitumor；Protein phosphatase；structural optimization；SAR