Preparation And Antitumor Mechanism Of Piperidinyl Thiosemicarbazide And Gallium(Ⅲ) Metal Complexes

Thiosemicarbazone metal gallium complexes have received some attention due to their good antitumor activity.Two types of piperidinylthiosemicarbazide ligands and Ga(Ⅲ)complexes were designed and synthesized.And its ability to inhibit tumor activity and mechanism were studied.The following is the main work of this paper:Two types of piperidinylthiosemicarbazide ligands and related Ga(Ⅲ)complexes were constructed,in which the first type of Schiff base contained a pyridyl group and the second type of Schiff base contained a Azinyl group.The ligands and complexes were subjected to NMR,high resolution mass spectrometry and X-ray single crystal diffraction to characterize its structure.Ultraviolet full-wavelength scanning of ligands and gallium(Ⅲ)complexes at different times indicated that the ligands and gallium(Ⅲ)complexes have good stability and the ligands are converted to gallium(Ⅲ)complexes structures immediately after adding gallium chlorine.The prepared ligands(L1-L7)and gallium complexes(Ga1-Ga7)were tested for tumor activity by MTT assay,and the effects of drugs on normal human lung cells were studied.The results showed that both the ligands(L1-L7)and the gallium complexes(Ga1-Ga7)had significant antitumor activity,and the ability of the gallium complexes(Ga1-Ga7)to inhibit tumor activity compared with the corresponding ligand was demonstrated to be improved.It was found that the antitumor activities of the first class ligand and the gallium complexes containing pyridyl groups were higher than those of the second type ligands and complexes containing pyrazinyl groups.And L4 is the best one in the first class Schiff base containing pyridyl group,while L5 is the best one in the second class Schiff base containing the pyrazinyl group.The cellular uptake rate of seven gallium complexes were studied.The results showed that the uptake rate of Ga1-Ga7 by MCF-7 cells was obviously higher than that of gallium chloride,indicating that complexes have better bioavailability,and the gallium complexes(Ga4 and Ga5)which also exhibit L4 and L5 perform best in the two types of compounds,respectively.In the apoptosis experiment,L4,L5,Ga4 and Ga5 had obvious pro-apoptotic effects compared with the blank control group.It is shown that the gallium complexes have a higher effect on promoting apoptosis of MCF-7 cells than the corresponding Schiff base ligand.The anti-tumor mechanism of the preferred drugs showed that the drug significantly up-regulated transferrin receptor-1 and down-regulated the expression of ferritin,and effectively activated the expression of Caspase-3/7/9,cytochrome cyt-c and apaf-1.These reveal that the anti-tumor mechanism of the drug is that the drug significantly deplete the cellular iron,activate the Caspase family protein(Caspase-3/7/9),promote the release of cytochrome from the mitochondria and forms a combination with the apoptotic protease activating factor apaf-1.Multimers eventually lead to apoptosis.