四氢原小檗碱类化合物的生物催化糖基化、拆分研究及活性评价

项目名称： 四氢原小檗碱类化合物的生物催化糖基化、拆分研究及活性评价

项目编号： No.21302052

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 葛海霞

作者单位： 湖州师范学院

项目金额： 25万元

中文摘要： 四氢原小檗碱类化合物（THPBs）是一类重要的活性天然产物，具有抗中枢神经系统疾病和抗心血管疾病等作用，是目前新药研发的热点化合物。申请者在前期开展的THPBs 结构修饰研究中，创造性的开展了自然界稀有的四氢原小檗碱糖苷的合成，并发现生物催化糖基化能对该类化合物进行动力学拆分和化学拆分，鉴于糖基化和拆分对于药物发现和改造的重要性，本项目将进一步深入该研究，结合化学方法在THPBs 的两个苯环引入不同的取代基，特别是羟基，制备结构类型多样的衍生物；利用各种生物催化体系（微生物、植物组织和酶）对含酚羟基的化合物开展糖基化研究，进一步挖掘新型催化体系，探索糖基化方法对THPBs的拆分应用，构建含有糖苷和苷元的THPBs 化合物库。同时选择多巴胺(DA)和组织因子（TF）作为分子靶标活性评价体系，围绕DA和TF开展分子模拟、体内外活性研究，分析构效关系，为新型先导化合物的发现提供研究思路和方法。

中文关键词： 四氢原小檗碱类化合物；生物转化；糖基化；生物活性；分子对接

英文摘要： Tetrahydroprotoberberines (THPBs), a class of abundant active natural products, have been demonstrated to possess various biological activities in the central nervous systems and the cardiovascular system and have become the hot spot compounds in the R&D of new drugs. In pioneer works studying the structural modification of THPBs, the applicant had creatively developed the synthetic method for the rare natural THPBs glycoside by biocatalysis. It was also found that the glycosylation by biocatalysis can separate the raceme THPBs by kinetic resolution and chemical resolution. Considering of the importance of small molecular glycosylation and resolution in new drug discovery and improvement, we will move on the research, prepare the structurally diverse THPBs derivatives through introducing different substituents on the two benzene rings with chemical synthetic method, especially hydroxyl. We will study glycosylation of THPBs containing phenolic hydroxyl using a variety of biocatalysis system (microbial, plant tissue and enzyme), and further develop new catalytic systems, and explore the resolution application of glycosylation methods on THPBs, and construct compound library containing THPBs glycosides and aglycones. Based on this library we will choose DA receptors and tissue factor as bioassay targets to carry ou

英文关键词： Tetrahydroprotoberberines；Biotransformation；Glycosylation；Bioactivity；Molecular Docking