Synthesis,Antitumor Activity And Mechanism Of 2-quinolinaldehyde Thiosemicarbazone Derivatives And Their Gallium Complexes

The?-N-heterocyclic thiosemicarbazone derivatives and their metal complexes showed excellent biochemical activity,especially in antitumor.Therefore,six kinds of2-quinolinaldehyde thiosemicarbazone derivatives and their corresponding gallium complexes were designed and synthesized in this thesis,and the structure,antitumor activity and antitumor mechanism of these compounds were studied.Six 2-quinolinaldehyde thiosemicarbazone derivatives?L1-L6?were obtained by reaction of Schiff base with 2-quinolinecarboxaldehyde and six thiosemicarbazides?thiosemicarbazide,N-methylhydrazinecarbothioamide,N,N-dimethylhydrazinecarb-othioamide,N,N-diethylhydrazinecarbothioamide,pyrrolidine-1-carbothiohydrazide and piperidine-1-carbothiohydrazide?.These six compounds were then separately reacted with gallium trichloride to obtain six gallium complexes with similar structural type?L1-L6?.Twelve compounds were characterized by¹H NMR,¹³C NMR,ESI-MS,elemental analysis and UV-vis spectroscopy.The gallium complex C6was also characterized by X-ray single crystal diffraction to determine the molecular structure.UV-visible spectroscopy studies have shown that these compounds are stable under physiological conditions.The in vitro antitumor activity of twelve compounds against human lung cancer cells?A549?,human gastric cancer cells?SGC-7901?and human normal liver cells?LO2?was determined by MTT assay and paralleled with the classical anticancer drug cisplatin.The IC₅₀0 values of these compounds towards tumor cells were all less than 20?M,and for normal cells were generally higher than 50?M.All compounds have better selectivity than cisplatin,and L6 and C6 have best antitumor activities.Cell cycle and apoptosis studies have suggested that both L6 and C6 can block cell cycle and promote cell apoptosis.Further studies on the antitumor mechanism of L6 and C6 showed that the antitumor activity of the gallium complex increased with the increase of the lipophilicity of the ligand.By detecting the ability of A549 cells to take up gallium chloride and six gallium complexes,it was observed that the content of gallium in A549 cells treated with organogallium complexes C1-C6 was much higher than that treated with gallium trichloride,indicating that gallium complexes were more easily taken up by tumor cell.Reactive oxygen species?ROS?analysis has demonstrated that gallium complexes significantly increase intracellular ROS.Membrane potential measurements indicate the collapse of mitochondrial transmembrane potential under the intervention of gallium complexes,a key feature of apoptosis induced by the mitochondrial pathway.Apoptotic protein analysis showed that 2-quinolinecarboxaldehyde thiosemicarbazone derivatives and gallium complexes can promote the activation of apoptosis-related proteins,and the gallium complexes are more effective than the corresponding ligands,which is consistent with the results of apoptosis analysis.