Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides
In order to find efficient antitumor compounds,19 novel 3,4-dichlorophenyl amides were designed and synthesized by introducing amide bonds and 3,4-dichloro substitution into the curcumin skeleton according to the principles of medicinal chemistry combination.The in vitro antitumor activity of the compounds against AGS and BGC-823 gastric cancer cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.The results showed that some com-pounds displayed potential inhibitory activity.Notably,(2E)-3-(3,4-dichlorophenyl)-1-(2-(3-(4-(trifluoromethyl)phenyl)propio-nyl)ethylazo)propan-2-en-1-one(17)showed potent growth inhibition on AGS with a half maximal inhibitory concentration(IC50)value of(1.94±0.94)μmol/L.Besides,the results of cell colony formation,wound healing,flow cytometry and western blot showed that compound 17 significantly inhibited the growth and migration of AGS cells,arrested the cell cycle in G0/G1 phase,and induced a dose-dependent up-regulation of the pro-apoptotic proteins such as cleaved poly ADP-ribose polymerase(Cleaved-PARP)and Bcl2-associated X protein(Bax),and a down-regulation of the anti-apoptotic protein Bcl-2,thus inducing cell apoptosis.Preliminary mechanistic studies suggested that compound 17 may exert its anti-gastric cancer effects in vitro by inhibiting dual-specificity tyrosine phosphorylation-regulated kinase 1A(DYRK1A)-protein kinase B(PKB,AKT)signaling pathway.In conclusion,this study indicates that amide compounds containing 3,4-dichlorophenyl may be a class of small molecule compounds with promising prospects for medicinal research,and compound 17 is expected to be an antitumor candi-date.
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