选择性识别G-四链体DNA的生物碱金属药物合成与机制研究

项目名称： 选择性识别G-四链体DNA的生物碱金属药物合成与机制研究

项目编号： No.21261025

项目类型： 地区科学基金项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 谭明雄

作者单位： 玉林师范学院

项目金额： 48万元

中文摘要： 端粒G-四链体DNA是抗肿瘤药物的潜在靶点，而天然产物一直是开发结构复杂多样抗肿瘤新药的宝贵源泉。本项目从丰富的植物资源中选择抗肿瘤活性成分吲哚喹唑啉类生物碱色胺酮（tryptanthrine）和吴茱萸次碱(rutaecarpine)的化学结构为研究基础，合成选择性识别端粒G-四链体DNA的天然活性成分金属配合物，并评价体外细胞毒活性和作用机制。通过杂环、卤原子和金属离子等结构修饰增加G-四链体稳定性；通过构-效关系分析，建立基于疏水中心、氢键贡献、金属离子作用等药效团模型，寻求结构、选择性和活性之间的内在联系和规律，为进一步筛选高效、低毒的抗肿瘤金属药物奠定实验和理论基础，对丰富和拓宽抗肿瘤药物的合成和筛选以及天然药物的研究和应用具有重要的意义。

中文关键词： G-四链体DNA；色胺酮；吴茱萸碱；吴茱萸次碱；金属配合物

英文摘要： Telomeric G-quadruplex DNA is a potential target for anticancer drugs，and the natural products have been an invaluable source for discovering potent anti-tumor drugs of diverse structures.A series of metal complex of natural active ingredients from indoloquinazoline alkaloids of tryptanthrine and rutaecarpine are synthesized basing on selective recognition quadruplex DNA, as well as their in vitro anticancer activity and mechanisms are investigated. The prominent strategies to stablize quadruplex DNA structures are explored by combining heterocycles, halogen and metal ions. The pharmacophore model and the mechanisms are formed based on hydrophobic center, hydrogen bond, halogen and metal ions, as well as the mechanisms of structure-function relationship. The results will provide the theoretical and technical foundation in defining the best strategy to prepare metal complexes as potential anticancer drugs. Taken together, the results will be of value for design and discovery of anticancer drug, and development of natural medicines.

英文关键词： G-quadruplex DNA；tryptanthrine；evodiamine；rutaecarpine；metal complex