Studies On Antitumor Activity Of New Iridium(Ⅲ) And Ruthenium(Ⅱ) Metal Complexes

Cancer,as a major disease threatening human life and health,has a low cure rate and a high mortality rate,which has caused a huge physical and mental burden to patients and their families.Although the medical environment has gradually become better with the development of economy and technology,there are still many challenges for cancer treatment due to the complex and diverse causes of development and evolution of cancer.Chemotherapy is the most common way to treat cancer.Among chemotherapeutic drugs,transition metal complexes play an important role.And platinum-based metal drugs,such as cisplatin,have achieved remarkable success in clinical application.However,these drugs could cause serious toxic side effects including ototoxicity and nephrotoxicity during the treatment of cancer.Therefore,scientific researchers have been working to develop other transition metal complexes with high antitumor efficiency and low toxicity.Among them,iridium（Ⅲ）and ruthenium（Ⅱ）metal complexes have shown good antitumor potential due to their excellent physical and chemical properties.In this paper,one iridium（Ⅲ）and four ruthenium（Ⅱ）metal complexes were synthesized.And high-resolution mass spectrometry,¹³C NMR and ¹H NMR were performed to characterize the structures.We then explored the antitumor activity and mechanism of the complexes in vitro and in vivo.First,MTT assays were used to examine the toxicity of the complexes on cancer cells.Then,endocytosis experiments were performed to observe whether the complexes could be effectively taken up by cells.Next,cell colony and scratching assays were carried out to investigate the proliferation inhibition of the complexes on tumor cells;And the effects of complexes on cell migration were evaluated by detecting the expression level of focal adhesion kinase FAK.Also,we examined the effects of the complexes on mitochondrial membrane potential,ROS levels,cytochrome C levels and autophagy by Image Xpress Mcro XLS.Further,flow cytometry was used to examine the effects of the complexes on autophagy,apoptosis,cell cycle as well as intracellular ROS.In addition,Bcl-2 family proteins and autophagy related proteins were detected by Western blot.And animal experiments were carried out to evaluate the in vivo antitumor activity and safety of the complexes.The results indicated that complexes showed favorable cytotoxicity towards cancer cells and less toxicity on normal cells.And endocytosis,cell cloning,cell scratching and cell cycle assays showed that complexes could efficiently inhibit cell proliferation and block the cell cycle at G0/G1 phase.In addition,we have also found that the complexes could induce apoptosis by targeting mitochondria and leading to mitochondrial dysfunction,including reducing mitochondrial membrane potential,increasing intracellular ROS levels and the release of cytochrome C from mitochondria.What’s more,the complexes exerted antitumor effects by promoting autophagy,regulating the expression levels of Bcl-2 family proteins as well as PI3K/AKT/m TOR signaling pathway.In vivo experiments,the complex2 synthesized in Chapter 1 showed good tumor-suppressive effects,but it cannot be ignored that the complex also caused a certain degree of liver and kidney toxicity.Therefore,the formulations are supposed to be further improved.In conclusion,the complexes we synthesized have excellent anticancer effects,and are expected to be developed into clinical anticancer drugs after further exploration and optimization.