Organometallic Iridium And Ruthenium Complexes:Synthesis And Antitumor Mechanism Of Action

Cancer has become one of the most urgent health care challenges that modern medicine faces today in which cancer metastasis and resistance phenomena are the two main intractable problems of cancer therapy in the clinic.Although tremendous efforts have been invested in research on cancer prevention,diagnosis and treatment,the cancer incidences and mortalities are rising.However,despite the applications of cisplatin and other platinum drugs are very popular and exhibit the anticancer efficacy toward lots of types of cancers,problems associated with their application are severe adverse effects and acquired drug resistance development.Consequently,it is of great significance for developing new metal-based anticancer complexes that overcome the limitations of platinum chemotherapics.Recently,a wide range of metal-based complexes Ir and Ru with the structural variability,modified ligands and anti-tumor mechanism of action that is different from cisplatin were developed with the aim of improving their anticancer activities.The anticancer research on Ir???and Ru???complexes has attracted considerable attention.For the above reasons,by changing the coordination type of the chelating ligands,we design and develop many types of new metal-based Ir???and Ru???complexes with high potency against cancer cell lines and the mechanism of action of anticancer and targets are investigated from multiple levels.These studies will compensate for shortages of clinical platinum drugs,and provide valuable theoretical basis for cancer treatment and development of new metal-based anticancer drugs.The brief introductions of results in this dissertation are shown as follows:1?We have designed,synthesized and authenticated a new class of Ir???-based complexes with phosphine-imine?P^N?ligands.These complexes show high cytotoxicity against many types of cancer cell lines in vitro.Simultaneously,antitumor mechanism studies display that complex Ir3 induce apoptosis by depolarization of mitochondrial membrane potential,ROS overproduction and ROS-mediated DNA damage.Importantly,BIX01294,a G9a histone methyltransferase inhibitor,could markedly sensitize Ir3-induced cytotoxicity,cell cycle arrest,apoptosis and inhibition of migration in HCT116 cancer cells in vitro.Finally,we show that BIX01294 could potently sensitize Ir???-based metal complexes-induced inhibition of tumor progression and lung metastasis in vivo.2?Herein we present four half-sandwich Ir???complexes[(?⁵-Cp^xbiph)Ir?O?C?Cl]containing O?C?NHC?-chelating ligand as anticancer agents.All the complexes displayed high potency in vitro against a wide range of cancer cells.Complex Ir2 can induce cell migration inhibition,depolarization of mitochondrial membrane potential,ROS overproduction and lysosomal damage.In addition,Ir2 significantly curb tumor growth in a colon cancer mouse xenograft model in vivo.Further mechanism of action studies indicate that Ir2-initiated apoptosis occurs through ROS-mediated cross-talk between mitochondria and lysosomes.3?Two half-sandwich Ru???diimine complexes have been synthesized and characterized as anticancer agents.Both Ru1and Ru2 complexes display high antiproliferative properties against various cancer cell lines.In addition,they exhibit no cross-resistance with cisplatin.The complexes target mitochondria,damage mitochondrial integrity,increase the ROS overproduction,and induce mitochondrial membrane permeabilization.Further antitumor mechanism studies display that the complexes can induce activation of caspase 3/PARP.Interestingly,the complexes finally lead to apoptosis and impede cell migration in cancer cells via ROS-mediated signaling.4?We have designed,synthesized and characterized five half-sandwich Ru???complexes[??⁶-cymene?Ru?N^N?Cl]PF₆ containing N^N?aryl-BIAN?-chelating ligand as anticancer agents.All complexes show high antiproliferative properties against a wide range of cancer cell lines in low micromolar range.Interestingly,in comparison with the complexes bearing electron-donating substituents?Me and OMe?,the complexes bearing electron-withdrawing substituents on the aryl rings?F,Cl,and Br?show higher anticancer properties.Additionally,the complex Ru1 could target lysosome,damage lysosomal integrity,and increase the Cathepsin B release.Importantly,inhibition of lysosomal enzymes could rescue the viability of cells and block the apoptosis induced by complex Ru1.Finally,complex Ru1 significantly inhibits tumor growth in a colon cancer CT26 mouse xenograft model in vivo.Taken together,these results show that these complexes could potently induce inhibition of tumor progression and provide the theoretical basis for developing new Ru-based anticancer drugs.