线粒体靶向磷光铱氮杂环卡宾配合物的细胞内催化活性及抗癌机制研究

The investigation of mitochondria-targeted anticancer drug and intercellular catalytic mechanism of metal-based drugs is becoming a very active topic at home and abroad. The objective of this project includes the design, synthesis and characterization of a series of mitochondria-targeted phosphorescent iridium N-heterocyclic carbene (NHC) complexes with catalytic activity, investigating their relationship between the structure and properties, preliminarily summarizing the general mitochondria-targeted rules of iridium complexes, screening the contribution of their catalytic properties for anticancer mechanism, and elucidating their targets and mechanisms at the molecular level, combining with new techniques such as confocal microscopy and PLIM (Phosphorescence Lifetime Imaging), will be used to real-time quantitatively monitored the dynamic process of mitochondrial autophagy and apoptosis. Based on the excellent catalytic properties and unique targeting of NHC complexes, and combining with excellent optical properties and anti-cancer activity of phosphorescent iridium complexes, the development of mitochondria-targeted anticancer metal drugs based on the intracellular catalytic mechanism, provide an important theoretical and experimental foundation for the development of mitochondrial diagnosis drugs with clinical potential.

线粒体靶向抗癌药物及金属药物的细胞内催化机理研究是目前国内外十分活跃的研究课题。本项目拟设计、合成和表征系列具有催化活性的线粒体靶向磷光铱氮杂环卡宾配合物，研究配合物结构与性能的关系，初步总结配合物线粒体靶向的一般规律，探究其催化性能对抗癌机制的贡献，在分子水平上阐明配合物的作用靶点和机制；利用激光共聚焦、PLIM（磷光寿命成像）等新技术对线粒体的自噬、细胞凋亡等过程实时定量监测。氮杂环卡宾配合物独特的靶向性和优异的催化性能，结合磷光铱配合物良好的光学性质和抗癌活性，发展基于细胞内催化机理的线粒体抗癌金属药物，为发展新型有临床应用前景的线粒体诊疗药物提供了重要的理论和实验基础。

线粒体作为真核细胞内的重要细胞器，在维持细胞的正常新陈代谢和调控程序化细胞死亡方面起关键作用。目前，开展线粒体靶向抗癌药物和荧光探针是国内外十分活跃的研究课题。本项目重点围绕线粒体靶向的铱氮杂环卡宾配合物和荧光探针开展工作；设计、合成了一系列具有抗癌和光动力治疗活性的铱、铼、钌配合物；研究这些配合物的光化学、光物理特性；利用配合物丰富的光化学性质，探索配合物在细胞中的定位；在细胞和活体水平研究配合物体内外抗癌活性、光动力治疗活性和作用机制；在分子、细胞、活体水平研究了探针分子对线粒体内硫醇的检测和成像；初步总结了化合物结构对其线粒体靶向性、抗癌活性和机制的影响。以上研究为寻找高效低毒的线粒体靶向抗癌药物和荧光探针提供了重要的理论基础和依据。