新型手性斑蝥素衍生物的设计、合成及抗肿瘤活性研究

项目名称： 新型手性斑蝥素衍生物的设计、合成及抗肿瘤活性研究

项目编号： No.21202142

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 有机化学

项目作者： 黄超

作者单位： 云南民族大学

项目金额： 25万元

中文摘要： 斑蝥素作为传统中药斑蝥的主要有效活性成分，在治疗恶性肿瘤疾病方面一直发挥重要作用，但由于毒副作用大、选择性差、药理机制不明确等影响了其进一步的应用。探讨斑蝥素关键部位的手性衍生化方法，利用失对称性制备光学活性斑蝥素衍生物，以蛋白磷酸酶PP1、PP2A为作用靶点，评价其抗肿瘤活性及酶抑制活性。为降低斑蝥素毒性、开发临床广泛应用的高效安全斑蝥素类抗肿瘤药物提供参考。 探讨斑蝥素分子C5，C6位不同取代基、构型对蛋白磷酸酶抑制和抗肿瘤活性的影响。以冰片烯与炔烃不对称金属催化反应构建单一光学纯、分子多样性斑蝥素衍生物库，系统评价其体内体外抗肿瘤活性，包括细胞毒活性、PP1和PP2A酶抑制活性、小鼠体内活性、急性毒性等。建立手性斑蝥素衍生物设计、合成及活性评价、构效关系研究体系。本项目的研究对于寻找新型高效低毒抗肿瘤化合物及手性药物具有重要的理论意义和广阔应用前景。

中文关键词： 斑蝥素；高立体选择性；分子多样性；生物活性；构效关系

英文摘要： Cantharidin plays an important role in the treatment of malignant diseases as the main effective constituents of Blister Beetle, which is one of Traditional Chinese Medicine used to cure tumors for a long time. However, further study has been hindered by its toxic side effects, poor selectivity and imprecision pharmacological mechanism. Research on the Protein phosphatase PP1, PP2A is expected by exploring cantharidin chiral derivatives method at critical parts, to prepare single optically pure cantharidin derivatives by breaking the symmetry and evaluate its antitumor and enzyme inhibitory activity. It is a reference to study reducing cantharidin toxicity, developing widely used efficient and safe cantharidin anticancer drugs in clinic. Study develops models to explore the effect about different cantharidin substituents and configuration at molecule C5, C6 on PP enzyme inhibition and anti-tumor activity. Single-optically pure and diversity cantharidin derivatives library are built by asymmetric metal-catalyzed reaction between norborneneand and alkyne. The anti-tumor activities in vitro and in vivo are evaluated, including the cytotoxic, PP1 and PP2A enzyme inhibitory and anticancer activity in mice and acute toxicity, and so on. A system study is expected around chiral cantharidin derivatives synthesis, biolog

英文关键词： Cantharidin；High selectivity；Molecular multiplicity；Biological activity；Structure-activity relationship