Chinese Journal of Organic Chemistry >
Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides
Received date: 2023-05-18
Revised date: 2023-08-16
Online published: 2023-09-15
Supported by
Natural Science Foundation of Zhejiang Province(LGF20B020001); Natural Science Foundation of Zhejiang Province(LGF21H160034); National Natural Science Foundation of China(81903074)
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 compounds 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.
Key words： curcumin analog; 3,4-dichlorophenyl; amide bond; synthesis; antitumor activity
Bozhen Wang , Jie Zhang , Chunhui Nian , Mingming Jin , Miaomiao Kong , Wulan Li , Wenfei He , Jianzhang Wu . Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides[J]. Chinese Journal of Organic Chemistry, 2024 , 44(1) : 232 -241 . DOI: 10.6023/cjoc202305025
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