Synthesis Of New Iridium(?) Metal Complexes Targeting Mitochondria And Studies On Antitumor Mechanism

With the significant improvement in medical and technological levels,chronic non-communicable diseases have gradually become the main cause of human death.As everyone knows,cancer has become one of the leading causes of death worldwide,which has caused great harm to human life and health.Therefore,it has become urgent for humans to find effective treatments to overcome the worldwide medical problem of malignant tumors.At present,the treatment of cancer can be roughly divided into chemical drug treatment,radiation therapy and surgical resection.Relying on its outstanding curative effect and wide applicability,chemotherapy is usually a preferred treatment method after comprehensive consideration.Among them,metal platinum?II?complexes have become one of the drugs of choice in current chemotherapy because of their broad anti-cancer spectrum,significant curative effect,and synergistic effects with various anti-tumor drugs.After extensive application,it was found that platinum drugs are prone to adverse reactions such as nephrotoxicity,neurotoxicity,and gastrointestinal damage.For this reason,scientists have been devoting to finding an ideal antitumor drug with significant effects,low side effects,and specific treatment.At the same time,the research on the antitumor activity of metal iridium complexes as the same main family as platinum has entered the field of scientific research.The work of this thesis is to synthesize and purify three series of small molecule metal iridium???complexes,and the complexes were characterized by ESI-MS,¹H NMR,¹³C NMR.Through in vitro evaluation of antitumor activity,it was found that these complexes have obvious cytotoxicity toward the selected tumor cell lines,and the antitumor mechanism in detail of the new compounds were investigated.The work in this thesis mainly explores the antitumor activity and mechanism of synthetic drugs on selected tumor cell lines from the following aspects:First,we tested the cytotoxicity of the complexes by MTT assay,and the results showed that the complexes have a significant effect on the inhibition of proliferation.Cell cloning experiment demonstrates that the complexes can effectively inhibit the cell colonies formation.Then,through subcellular organelle localization detection and AO/EB double staining experiment,the results show that the drug can enter into the cell and initiate tumor cell morphology apoptosis.Qualitative and quantitative analysis of endogenous reactive oxygen species levels,mitochondrial membrane potential changes,and calcium ion concentrations in high-content cell imaging analysis systems and flow cytometry show that all complexes can increase intracellular calcium ions concentration,induce a decrease of the mitochondrial membrane potential,and the reactive oxygen levels were significantly increased.Flow cytometry was used to detect changes in tumor cell cycle and apoptosis after the cancer cells were treated with the complexes,and it was found that the cell growth was clearly blocked at a certain stage,and the complexes cause early apoptosis.In addition,through immunoblot experiments to investigate the signaling pathways of tumor cell apoptosis,it was found that the expression of the mitochondrial-associated protein Bcl-2 family has significantly changed.Therefore,the results show that metal iridium???complexes induce apoptosis by mediating signal molecules of target mitochondria.