Study On The Synthesis And Antitumor Mechanism Of New Ruthenium,Iridium Polypyridine Complexes

Cancer has become one of the most serious diseases in the world due to its high fatality rate.With the development of economy,the incidence of cancer is increasing.The demand for safe and effective therapeutic drugs is increasing.Platinum(?)metal complexes represented by cisplatin have been widely used in clinical combined chemotherapy because of their broad anticancer spectrum.However,with the advancement of treatment,the serious defects of platinum drugs,such as strong side effects,poor water solubility,cross-resistance and poor selectivity,limit their further application in clinic.Therefore,it is urgent to develop new metal complexes with high efficiency,low toxicity,selectivity,targeting and no cross-resistance.More and more researchers have also turned their attention to transition metals such as ruthenium and iridium,which belong to the same group as platinum.Under the guidance of rational drug design principles,a series of ruthenium(?)complexes and three series of iridium(?)complexes were synthesized and purified by using ruthenium(?)and iridium(?)as central metal atoms.The molecular structures of the complexes were characterized by ultraviolet,infrared,mass spectrometry and nuclear magnetic resonance spectroscopy.The anti-tumor activity and mechanism of the complexes were studied in vitro and in vivo by means of biochemistry and cell biology.In vitro experiments,MTT assay was used to detect the cytotoxicity of the complexes to each cell line.It was found that the complexes had a good inhibitory effect on specific cell lines.Through subcellular localization experiments,AO/EB and Hoechst 33342 staining experiments,we found that the complexes could enter cellsand cause the cell to shrink and round,leading to cell apoptosis.Quantitative analysis by flow cytometry showed that the complexes could induce apoptosis,and the ability to induce apoptosis was related to the content of intracellular reactive oxygen species.Fluorescence microscopy,ImageXpress Micro XLS,flow cytometry and Western blot analysis showed that the complexes could affect cell division by destroying DNA and inhibiting the depolymerization of tubulin,leading to cell cycle arrest and inducing cell apoptosis.In addition,the complex can increase the release of intracellular reactive oxygen species(ROS)to induce the release of calcium ions,which leads to the collapse of mitochondrial membrane potential and the release of cytochrome C from mitochondria to cytoplasm,and activate mitochondrial-dependent endogenous apoptotic pathway by up-regulating the expression of Bax/Bcl-2.More importantly,the drug can also cause autophagy by affecting lysosomes,further leading to apoptosis.These results suggest that the complexes can induce apoptosis in many ways to inhibit the growth of tumors.In addition,we tested the antibacterial activity of some ruthenium(?)complexes and found that the complexes have certain antibacterial activity.In addition,we have further studied the antitumor activity of a complex in vivo.Firstly,we established a xenograft model of human gastric cancer SGC-7901 in nude mice.Then the nude mice were randomly divided into four groups to observe the growth of tumors,the changes of ALT content in blood and the histological changes of liver and kidney by HE staining.The results showed that compared with the control group,the growth rate and volume of tumors in the drug group were relatively slow,and HE staining showed that the complex had little effect on the liver and kidney of mice.These results indicate that iridium(?)complex also has good antitumor activity in vivo.