芳基钌、锇抗癌配合物与DNA相互作用及抗癌机理研究

芳基金属配合物抗癌研究近年来取得较大突破，一批药物已进入前期临床试验。它们在细胞中的可能靶点是DNA，研究其与DNA的作用并阐明抗癌机理十分重要。动力学方法研究药物与靶点的作用全过程并对作用机理给出科学合理的解析，是药物研究的热点，但芳基金属配合物与DNA的动力学研究尚属空白。.在前期工作基础上，本项目应用组合学方法，系统研究代表性芳基钌、锇配合物与DNA的作用；测定反应速率和程度，获得热、动力学信息，建立动力学模型，从动力学角度解析芳基钌、锇配合物与DNA作用机理；解析DNA-配合物加合物溶液结构，探讨芳基钌、锇(II)配合物的作用类型及方式（配位键合位点及方式、配位键数目、单嵌入及多重嵌入）对DNA嵌入作用、DNA损伤的影响，以及上述作用与配合物抗癌活性的关系及规律性。这些对于探索药物的抗癌机理、筛选高效低毒的抗癌药并指导临床合理用药，及合理的药物设计有重要指导作用及实用价值。

Metal-arene complexes have achieved major breakthroughs as anticancer drugs and several of them have entered preclinical trials. The potential target for these drugs in cell is DNA. The kinetic studies of the interactions between drugs and DNA is very important and is one of the hot research field in drug development. It can help for the rational design of new DNA-binding agents that recognize specific sequences or structures, and can modify specific DNA functions, provides an effective approach for development of novel chemotherapeutic anticancer drugs. However, there are no reports about the kinetic studies of the interactions between metal-arene complexes and DNA so far. A number of novel bifunctional ruthenium/osmium complexes with polycyclic aromatic ligands have been systematically synthesized and characterized in our lab. In this project, the interaction mechanism of representative Ru/Os-arene complexes with DNA will be studied via combinative methods including multi-dimensional NMR, and the factors which can influence the anticancer activities, such as the types of arene, coordinative sites, mono-, dual-intercalation, types of DNA lesion will be elucidated. The interaction mechanism with DNA will be investigated via kinetic methods by using 2D [1H, 15N] HSQC and [1H, 31P] HSQC NMR. The thermokinetics model and thermodynamic functions of interactional effect between Ru/Os-arene and DNA，will be set up or calculated, the types of effect and specialities of thermokineties will also be summarized，these results will provide important information for the exploration of the effect mechanism between anticancer drugs and DNA. This research will set up a solid theoretical foundation for further research, and such knowledge may contribute to designing and synthesis of high selectivity, high activity and low toxicity anticancer drug and assist to establish the relationship between the structures of complexes and their anticancer activities.