靶向组蛋白去乙酰化酶的金属有机铂/铱配合物抗肿瘤活性及机制研究

项目名称： 靶向组蛋白去乙酰化酶的金属有机铂/铱配合物抗肿瘤活性及机制研究

项目编号： No.21201183

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 无机化学

项目作者： 谭彩萍

作者单位： 中山大学

项目金额： 25万元

中文摘要： 组蛋白去乙酰化酶在基因表达和染色质重组等方面起着重要的调节作用，是目前肿瘤治疗重要的分子靶点之一。组蛋白去乙酰化酶抑制剂能够抑制肿瘤细胞生长、阻滞细胞周期、诱导肿瘤细胞分化和凋亡，且对正常细胞毒性很低。最近研究表明，金属配合物由于其多样可控的三维结构，可作为高效的蛋白酶抑制剂。本项目以组蛋白去乙酰化酶为靶点，设计、合成一系列的含靶向组蛋白去乙酰化酶活性基团的铂、铱金属有机配合物；研究这些配合物的光化学、光物理特性；在分子水平研究配合物与靶点的亲和力、选择性和结合模式；利用金属有机铂、铱配合物的光化学性质，探索配合物在细胞中的吸收和定位；在细胞水平研究配合物体外抗肿瘤活性和作用机制、对组蛋白乙酰化水平的影响以及对下游相关基因表达的调控；初步总结配合物的结构与对组蛋白去乙酰化酶的抑制活性以及对细胞生理过程的影响之间的关系。以上研究为寻找高效低毒的金属基靶向型抗肿瘤药物提供重要的理论基础。

中文关键词： 组蛋白去乙酰化酶；铱配合物；钌配合物；抗肿瘤；

英文摘要： Histone deacetylases play important roles in gene expression and chromatin reorganization, and they are among the most promising current molecular targets for cancer therapy. Histone deacetylase inhibitors show potent growth inhibitory effects on cancer cells, which involves alterations in proliferation (cell cycle progression), differentiation and apoptosis. Most importantly, they show very low toxicity to normal cells. Recent studies have shown that, due to their diverse and controllable three-dimensional structures, metal complexes can be used as efficient kinase inhibitors. A series of organometallic platinum and iridium complexes containing histone deacetylase targeting groups is designed in this project. The synthesis, photochemical and photophysical properties of these complexes will be studied. The in vitro studies of the binding affinities and binding modes of the complexes with histone deacetylases will be explored. Due to their rich physiochemical properties, the absorption and localization of the complexes in cancer cells can be easily studied by fluorescence microscopy. The studies on the in vitro anticancer potencies and mechanisms of the complexes, the toxicity of the complexes towards normal cells, the impact of the complexes on histone acetylation levels and expression of related genes will be c

英文关键词： Histone Deacetylase；Iridium Complex；Ruthenium Complex；Anticancer；