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

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 carried out. The relationship between the structures of the complexes, the inhibitory activities on histone deacetylase as well as the impact on cellular processes of the complexes will also be explored. The above studies will provide important theoretical basis for the search for metal-based targeted anticancer drugs of high efficiency and low toxicity.

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。

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。我们以组蛋白去乙酰化酶为靶点，设计、合成一系列的金属钌、铱和铼配合物作为多功能抑制剂。我们研究了这些配合物在体外对组蛋白去乙酰基酶的抑制作用，在细胞水平探索配合物在细胞中的吸收和定位、配合物体外抗肿瘤活性和作用机制以及对组蛋白乙酰化水平的影响。除了组蛋白去乙酰基酶，我们还研究了金属配合物作为细胞周期素依赖性激酶抑制剂，自噬溶酶体诊疗剂以及溶酶体靶向的光动力治疗药物等。通过该项目的研究，在Angew. Chem. Int. Ed.、Chem. Sci.、Biomaterials等杂志上发表标注本项目的SCI收录论文共10篇，其中影响因子>5.0的论文9篇。申请了2项国家公开发明专利，其中1项获得授权。协助培养博士生2名，硕士2名。资助期间，项目负责人获得了广东省杰出青年基金。

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