低温真菌来源α-吡喃酮类分子的抗肿瘤活性及作用机制研究

项目名称： 低温真菌来源α-吡喃酮类分子的抗肿瘤活性及作用机制研究

项目编号： No.81202416

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： 李彦

作者单位： 中国人民解放军军事医学科学院

项目金额： 23万元

中文摘要： 癌症是严重危害人类健康的重大疾病之一。从真菌资源中寻找抗肿瘤活性次生代谢产物是发现抗肿瘤先导化合物的重要途径之一。本项目基于申请人在低温真菌次生代谢产物的结构和药理活性方面的研究积累，以从一株矛束霉属（Doratomyces sp.）低温真菌中发现的具有显著体外抑瘤活性的α-吡喃酮类次生代谢产物Rasfonin及其同系物为导向，结合体外抑瘤活性评价以及LC/UV/MS指导的化学筛选，应用多种分离技术从产生菌的放大发酵提取物中大量富集Rasfonin，并快速、高效地发现其它结构类似的抗肿瘤活性成分。在此基础上，对Rasfonin进行结构修饰，制备系列衍生物，并与分离的其它类似物的抑瘤活性比较、分析，探索构效关系，获得值得深入研究的目标化合物，对其开展初步抗肿瘤作用机制研究与体外快速ADME评价，为抗肿瘤先导化合物的发现提供依据。

中文关键词： 低温真菌；α-吡喃酮类；抗肿瘤活性；作用机制；构效关系

英文摘要： Cancer is one of the major diseases with serious harm to human health. Looking for fungal secondary metabolites with anti-tumor activity is one of important ways to find anti-tumor lead compounds. The project is based on our early research on the aspects of the structure and pharmacological activity of the secondary metabolites from the psychrotolerant fungi and the discovery of the α-pyrone class secondary metabolites Rasfonin and its derivatives with significant cytotoxic activity from a psychrotolerant fungus (Doratomyces sp.). In vitro anti-tumor activity evaluation, chemical screening guided by LC/UV/MS as well as various separation techniques are applied to largely enrich Rasfonin and to discover other anti-tumor α-pyrones from the amplification fermentation extract of this fungus. And then, we will explore the structure-activity relationships (SAR) by comparison and analysis of the cytotoxic activity of Rasfonin, its synthetic derivatives and other isolated natural analogues to obtain the target compounds for further research on their anti-tumor mechanism and the rapid ADME evaluation in vitro, thereby providing the basis for the discovery of anti-tumor lead compounds.

英文关键词： Psychrotolerant Fungi；α-Pyrones；Anti-Tumor Activity；Mechanism；SAR