[N,N] Ligand Half-sandwich Structure Iridium Anticancer Drug Design And Synthesis And Anticancer Mechanism Research

In recent years,malignant tumors show a high incidence in the world,more and more attention has been paid to the development of new anti-cancer drugs.Since platinum-based antitumor agents represented by cisplatin have been found to have good anticancer activity,this has aroused great interest in the anticancer properties of metal complexes,and demonstrated unique drug resistance,which has opened up new fields in anticancer drugs.The drug resistance and side effects of platinum drugs severely limit their efficacy and application in clinical treatment,so a large number of new metal compounds have been studied in the field of antitumor.In recent years,iridium compounds exhibit good antitumor properties,more and more iridium anticancer drugs have been studied and reported.In addition,it has been found that iridium complexes were displaying novel anticancer mechanism of actions?MoAs?different from platinum drugs,and showing high antiproliferative activity against cisplatin-resistant cancer cells,thus could be potential candidates for treatment of platinum resistant cancers.A series of novel organometallic half-sandwich Ir^{I I I} complexes of the type[??⁵-Cp^x?Ir?N^N?Cl]PF₆?A1-A8,B1-B15?,where Cp^x=C₅Me₅?Cp*?,C₅Me₄C₆H₅(Cp^xph),C₅Me₄C₆H₄C₆H₅(Cp^xbiph),N^N is imionopyridine and?-diimine chelating ligand,were prepared and characterized in the thesis.The structure,composition,anticancer mechanism of the complexes were studied by single crystal X-ray diffraction,UV-vis,¹H NMR,elemental analysis,mass spectrometry,etc.The catalytic hydrogen transfer activity of NADH was studied by UV-vis and ¹H NMR spectroscopy.The inhibitory activity of all novel organometallic half-sandwich Ir^IIIII complexes on human lung cancer cells?A549?was investigated by MTT assay,and the cell cycle,apoptosis and reactive oxygen species?ROS?production were also studied by flow cytometry.The crystal structures of A3 and B1 were determined.The hydrolysis of complexes A1,A2,A5,A8 and B1-B15 was studied by UV-vis and ¹H NMR spectroscopy,the experimental results show that the hydrolytic properties of the complexes are greatly affected by the structural changes of the complexes.The study of the catalytic NADH hydrogen transfer activity of complexes A1,A2,A5-A8 and B7-B9 was studied by Using UV-vis and ¹H NMR spectroscopy.The experimental results show that the organometallic half-sandwich Ir^III complexes in the study can convert NADH to the oxidized form NAD⁺.Compounds A2 and B9 showed high catalytic properties(TON_A2=25.4;TON_B9=29.9).The extent of formation of nucleobase adducts by complexes A1,A2,A5 and A8 based on ¹H NMR peak integrals was studied,compared with9-methyladenine,the complex A8 and 9-ethyl guanine showed strong binding ability.However,in comparison to A8,complexes A1 and A2 displayed weaker interaction with9-MeA;No reaction with 9-EtA or 9-EtG was noted for A5.Except for complex A3,the rest twenty-two complexes were all active against A549 cell line,displaying IC₅₀ values range from75.9 to 1.7?M.Complexes A1 and B9 showed high anticancer activity.Complex A1 was 12times higher than clinical anticancer drug cisplatin,and complex B9 was 6 times higher than clinical anticancer drug cisplatin.In general,the anticancer activity can be tuned by varying both Cp*-based ligands and iminopyridine ligands,in the order of Cp^xbiph>Cp^xph>Cp*.In addition,the anticancer mechanisms of A5,A8 and B9,which have good anti-cancer activity,were also studied.Compared with untreated cells,the cells treated with A5,A8 and B9 had obvious induction of apoptosis.Therefore,both complexes A5 and A8 dramatically induced apoptosis of A549 cells in a dose-dependent manner.Complex A5 mainly induces late apoptosis,while complex A8 mainly concentrates on early apoptosis.Compared with the control group,the complexes A5 and B9 interfered with cell cycle in G₁ phase,the complex A8 interfered with cell cycle in S phase and G₂/M phase compared with untreated cells,both A5 and A8 could significantly increase the level of reactive oxygen species?ROS?,and the ROS level of complex A5 was higher than that of A8.