Antitumor Activity And Mechanism Of The Novel Aromatic Heterocyclic Bearing Triazole Hybrids Derivatives

A new series of aromatic heterocyclic triazole derivatives were designed,synthesized.In this paper,the compounds were screened by MTT assay,and the compound H27 was found to have good anti-tumor activity.To further explore its mechanism of action,the anti-tumor activity of this compound was further studied through a series of experiments and evaluation.The specific research results are as follows:1.The anti-proliferative activity of this series of derivatives was screened by MTT assay with three cancer lines(MGC803,PC3 and EC109),fluorouracil was used as a positive control drug.The results show that the anti proliferative activity of compound H27 is the best.2.The antiproliferative effect of compound H27 especially on gastric cancer MGC803 cells with IC50 ranged from 7.31 to 7.87?M,while GES1 was less toxic to human normal gastric epithelial cells(IC50 31.71 ± 1.24 ?M).3.Through Cell growth curve and colony formation assay experiments,we found that compound H27 can slow down the growth of gastric cancer MGC803 cells and inhibit the proliferation of cells with dose-time dependent.4.Treated with different concentrations of compound H27 for 48 h in gastric cancer MGC803 cells by cell cycle assay kit.This shows that compound H27 can block gastric cancer MGC803 cells in G2/M phase,thus affecting the proliferation of cancer cells.The results of Western Blotting showed that the compound H27 blocked G2/M phase by regulating the expression of CyclinB1,CDK1 and p21.5.After the compound H27 was applied to MGC803 cells in gastric cancer cells,we found that apoptosis of cells was observed by morphological observation.6.We tested the effect of compound H27 on gastric cancer MGC803 cells by FITC-Annexin V / PI apoptosis kit for 48 h.The results of flow cytometry showed that the apoptosis rate was increased with the increase of compound H27 concentration.7.We detected the effect of compound H27 on gastric cancer MGC803 cells by the mitochondrial membrane potential detection kit(JC-1)for 48 hours.The results of flow cytometry showed that the more the compound H27 concentration,the more the mitochondrial membrane potential decreased.The result of Western Blotting showed that H27 could regulate the expression of Bcl-2 family protein and activate Caspase-9 and Caspase-3,eventually leading to the cleavage of PARP and the induction of apoptosis.8.The effect of compound H27 on gastric cancer MGC803 cells at different concentrations for 48 h.Western Blotting showed that the compound may activate DR4-mediated exogenous apoptosis Death pathway,Activated DR4 acts on Caspase-8 induces apoptosis.9.Through the scratch test and Transwell,compound H27 was found to reduce the invasion and metastasis of gastric cancer MGC803 cells.Compound H27 could reduce the expression of MMP-9 and Vementin protein by Western Blotting.In summary,the present paper effectively proved that the new aromatic heterocyclic triazole derivatives H27 have good selectivity for gastric cancer cells,especially gastric cancer MGC803 cells,the study demonstrated that the low concentration of compound H27 can effectively inhibit proliferation,invasion and metastasis of gastric cancer MGC803 cells,high concentrations induce apoptosis.It provides an important candidate compounds for the development of new drugs.