花椒属苯并菲啶衍生物的合成、抗癌作用机制和构效关系研究

项目名称： 花椒属苯并菲啶衍生物的合成、抗癌作用机制和构效关系研究

项目编号： No.31300286

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 彭进松

作者单位： 东北林业大学

项目金额： 23万元

中文摘要： 苯并菲啶生物碱是芸香科植物次生代谢的一类天然产物，其抗肿瘤生物活性因在人类疾病治疗中发挥着重要作用而备受关注。本项目将围绕高效低毒抗肿瘤药物开发主题，开展苯并菲啶天然产物的结构修饰、改造与优化研究，发现和发展一些高效、简洁和高选择性的合成方法，实现结构多样性苯并菲啶衍生物的化学合成；采用四氮唑盐还原法和磺酰罗丹明B蛋白染色法离体测定化合物对乳腺癌MCF-7、肝癌SMMC-7721细胞生长的抑制活性；利用紫外、荧光、圆二色谱及粘度测试方法研究化合物与DNA-拓扑异构酶复合物之间的相互作用，利用荧光偏振、等温滴定量热和二维核磁共振滴定研究Bcl-XL蛋白靶向的结合模式，阐明药物作用机制；应用Hansch-Fujita、CoMFA分析法和分子对接技术建立定量构效关系，阐明分子结构、空间构型、功能基团与生物活性之间的内在规律，为进一步开发抗肿瘤药物提供理论依据。

中文关键词： 苯并菲啶生物碱；结构修饰；化学合成；抗癌活性；构效关系

英文摘要： Benzophenanthridine alkaloids are a family of natural N-containing compounds that widely distributed in Rutaceous plants and display obvious antitumor activities against human tumor cell lines, playing an important role in disease control and having attracted much attention in medicinal chemistry over the past several decades. Aiming to develop natural products-based anticancer agents, this proposed research will (a) perform the structural modification and optimization of benzophenanthridine natural products, (b) discover and develop efficient and selective synthetic methods as powerful tools for the preparation of benzophenanthridine derivatives featured by structural diversity and complexity, (c) evaluate the antitumor effect on tumor cell lines MCF-7 and SMMC-7721 in vitro by using microculture tetrazolium assay (MTT) and sulforhodamine B (SRB) proteochromosonic assays, (d) explore the molecular mechanisms of compounds against DNA-topoisomerase complexes or Bcl-XL protein by fluorescent, UV-vis, CD spectroscopic techniques and viscosity measurement, or FP, ITC and 2D-NMR respectively, (e) acquire novel structures, pharmacophore definition, and scaffold hopping through quantitative structure-activity relationship analysis (Hansch-Fujita, CoMFA and molecular docking). Results of this research will help improve

英文关键词： benzophenanthridine alkaloids；structural modification；synthesis；antitumor activity；structure-activity relationship