Design,Synthesis And Bioactivity Exploration Of Ag(I) Complex

Cancer is one of the major diseases threatening human health in the world today.The discovery of cisplatin has stimulated the development of metal complexes as antitumor drugs.Ag(I) with antibacterial and antitumor biological activities has received widespread attention.The multidentate ligand-terpyridine is easy to be modified and chelated with various metals.Its metal complexes have been widely applied in many fields such as photoelectric materials and antitumor drugs.Triclotriazine has attracted extensive attention because of its easy modification and p-electron-deficient properties.In the literature,most reports about the tribipyridine-Ag(I) complexes are focused on their supramolecular or optical properties,and relatively few reports are about their anti-tumor properties.In this thesis,a series of Ag(I)complexes were designed and synthesized,and their biological activities were studied comprehensively.The antitumor activity was studied from the cellular level,the mechanism of damage to isolated mitochondria was investigated from the organelle level,and interaction with HSA was researched from the biological macromolecular level.This thesis is mainly divided into the following five parts:1.A series of ligands with good luminescent properties and their corresponding Ag(I)complexes were synthesized and characterized by MS,NMR and X-ray single crystal diffraction.The crystal structures indicated that the Ag(I)complexes displayed a hexa-coordinate octahedral configuration.The weak interactions within the crystals were also discussed.The structure-activity relationship between the optical properties and the chemical structure,and their solvent effects were examined by UV-vis and fluorescence spectra.2.The biological activity of the Ag(I)complexes were studied.Firstly,complex 3b with the best toxicity was screened out through MTT assay,and then it was used for further mechanism research.Co-localization experiments indicated that 3b could enter into mitochondria and lysosomes.In relation to mitochondria,3b triggered the increase of intracellular ROS content,the decrease of mitochondrial membrane potential,and the mitochondrial mediated apoptosis.In connection with lysosomes,3b induced the accumulation of autophagosomes in the cells,triggered autophagy and inhibited autophagy flux.Then the relationship between apoptosis and autophagy was further studied.The results indicated that autophagy was a protective process for the cell.3.The damage mechanism of 3b to isolated mitochondria was investigated.The in vitro mitochondria of the rat liver were extracted and purified efficiently,and then the mechanism action was explored by UV-vis,fluorescence,multi-function micro-plate reader,respiratory oxygen consumption and other techniques.The results showed that 3b induced mitochondrial swelling,collapse of membrane potential,decrease of membrane fluidity,the release cytochrome c and decrease of ATP content.Moreover,3b also caused mitochondrial respiratory dysfunction and reduced the activity of complex II and IV on the respiratory chain.4.After the drug enters the bloodstream,it will first interact with the proteins in the plasma.The interaction with the protein will affect the absorption,transport and distribution of the drug.Therefore,we studied the interaction between 3b and HSA.UV-vis,fluorescence and CD spectra were applied to test the mechanism of action.The results indicated that 3b quenched the endogenous fluorescence of HSA in a dynamic process.The type of interaction is entropy driven hydrophobic action.There were no influences in the microenvironment of the tryptophan and tyrosine residues.Moreover,3b had no effect on the second structure of HSA.5.Based on the previous experiments,we obtained a series of halogen-substituted cyclic thiourea complexes.Then we studied their antitumor biological activity and mitochondrial toxicity mechanism.The results showed that the cytotoxicity of Cl-substituted complex Ag Tu Cl and Au Tu Cl was the strongest,and the toxicity of Ag(I)was stronger than that of Au(I).Both the Ag Tu Cl and Au Tu Cl were capable of inducing caspase-dependent apoptosis in the mitochondrial mediated pathway.Moreover,they also triggered the mitochondria swelling and the disturbance of mitochondrial respiratory function,impairing the structure and function of mitochondria.