[P,O] And [N,N] Chelating Ligand-containing Iridium And Ruthenium Anticancer Complexes: Synthesis, Characterization And Mechanism Of Action

A new area has been opened up in the field of inorganic drugs by Rosenberg who discovered cisplatin's biological activity.Since then,carboplatin and oxaliplatin have been invented and widely used.Because of these drugs are limited by severe side effects and drug resistance,people began to explore other metal-based diagnostic and chemotherapeutic drugs.Among these study,organometallic half-sandwich iridium(?)and ruthenium(?)complexes and cyclometalated iridium(?)complexes have attracted a lot of interest because of their good anticancer activity and selectivity on various cancer cell cultures and the different mechanism of actions from clinical platinum drugs.A total of 27 complexes of four systems were synthesized,including 16 half-sandwich structure iridium complexes,7 half-sandwich ruthenium complexes,and 4 cyclometalated iridium complexes.In the study of this paper,we first modified the ligands and synthesized a series of half-sandwich iridium(?)and ruthenium(?)complexes containing[P,O]chelated ligands,corresponding to the second and third chapters of the paper.Secondly,we synthesized a series of cyclometalated iridium(?)complex containing[P,O]chelated ligands,corresponding to the fourth chapter of the paper.Next,we modified the Cp~x and synthesized a series of[N,N]five-coordinated half-sandwich iridium(?)and ruthenium(?)complexes,corresponding to the fifth chapter of the paper.The structures of these complexes were studied by single crystal X-ray diffraction,UV-vis,NMR,elemental analysis and mass spectrometry.Spectroscopic properties of these complexes were studied.The solution stability and catalytic NADH hydrogen transfer activity of complexes were studied by UV-vis and ~1H NMR spectroscopy.The cytotoxic activities of complexes against human HeLa cervical cancer cells,human lung cancer A549 cells,hepatoma cells HepG2 and two human bronchial epithelial normal cells(BEAS-2B and 16HBE)were investigated by MTT assay,and the cell cycle,apoptosis,reactive oxygen species production and mitochondrial membrane potential were also studied by flow cytometry.Investigate the microscopic mechanism about cellular localization,cell uptake and lysosomal damage by confocal microscopy.By studying these complexes we found that introduce the[P,O]chelated ligand or change the Cp~x can increase the anticancer activity.Five-coordinated half-sandwich iridium(?)and ruthenium(?)complexes were serendipitous synthesized by one-step,they have good stability and anticancer activity.These found provided a new direction and strategy for the future research of anticancer drugs.