Synthesis Of Half-sandwich Metal Complexes Of Ruthenium And Cyclometallic Iridium And Their Anticancer Activity In Vitro

In today’s world,with the aging of the population and people’s unhealthy lifestyles,the incidence and mortality of cancer are still rising.The development of antitumor drugs,especially transition metal complexes,has always been the focus of attention.Cisplatin and its derivatives have been considered essential drugs in clinical chemotherapy for the past 50 years,but their dose-dependent and severe side effects are not negligible.Therefore,the development of other new transition metal complexes has received widespread attention.This thesis focused on the synthesis and biocharacterization of five half-sandwich ruthenium(II)complexes(1-5)with iminopyridyl as ligands and six cyclometalated iridium(III)complexes(Ir1-Ir6)with imine-N-heterocyclic carbenes as ligands.The crystal structures of the complexes 4 and Ir4 were obtained by the culture.The purity and structure of the compounds were characterized by UV-Vis,nuclear magnetic spectroscopy,elemental analysis,X-ray single crystal diffraction and mass spectrometry.The anticancer activity of the compounds to different cancer cells and normal cells was tested by MTT assay(3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide),and the complexes were screened for subsequent anticancer mechanism.The main contents as follows:1.Design and synthesis of five half-sandwich ruthenium complexes containing iminopyridyl ligands.The toxicity of Ru complexes and cisplatin on cancer cells(cervical cancer cells(Hela),lung cancer cells(A549)and normal cells(human bronchial epithelial cells(16HBE and BEAS-2B))was tested by MTT assay.Both complexes showed good anticancer activity and selectivity,especially complex 5.The confocal microscopy was used for the first time to determine the cellular imaging of the half-sandwich Ru complex,and the complex was found to have lysosomal targeting,and then the lysosomal damage caused by the complex was monitored.Interestingly,more mechanistic studies have shown that complexes enter cancer cells through non-energy-dependent pathways,which then lead to mitochondrial dysfunction and excessive ROS to promote apoptosis.However,under the same conditions,normal cells have no obvious damage.In addition,the catalytic oxidation of the coenzyme NADH,the antimetastatic properties of the complex,and the interaction with BSA were also investigated.2.Six cyclometalated iridium complexes were designed and synthesized by using the imine-N-heterocyclic carbenes(NHCs)as ligand.The results of MTT assay showed that the six complexes showed good toxicity to all five cancer cells(cervical cancer cells(Hela),lung cancer cells(A549),liver cancer cells(HepG2),mouse glioma cells(GL261),and resistant cisplatin cells(A549R)).In particular,the anticancer activity of the complex Ir6 up to 9 and 37 times more potent than clinical used anticancer drug cisplatin towards A549 and A549 R cell lines,respectively.Therefore,we conducted a series of investigations on the complex Ir6.HPLC-UV showed that the complexes are stable in a bioactivities test environment.The anticancer mechanism of the complex showed that the complexes mainly pass into cancer cells through an energy-dependent pathway,resulting in apoptosis via mitochondrial membrane potential dysfunction,ROS production and lysosomal damage.At the same time,the complex exhibits strong antimetastatic ability and ability to bind to DNA.