OBJECTIVE To design and synthesize novel CDK9 inhibitors 1-(2-adamantan-1-yl-1H-indole-5-yl)-3-substituted thiourea derivatives and study their anti-gastric cancer activities.METHODS A series of target compounds 7a-7m were synthe-sized from adamantan formyl chloride by 6-step reactions.The structures of the target compounds were identified by 1H-NMR,13C-NMR,and HRMS.MTT assay was used to detect the inhibitory effect of synthetic compounds on the growth of gastric cancer cells,ADP-Glo kinase assay was used to detect the effect of synthetic compounds on CDK9 kinase activity and Western blot assay was used to detect the regulatory effect of hit compound on downstream signaling pathways.RESULTS The target compounds had certain inhibitory activity on the growth of gastric cancer cells,among which compound 71 had the best activity on the gastric cancer cell line(SGC-7901)with IC50 value of(2.26±0.04)μmol·L-1,and 71 had little toxicity on normal gastric epithelial cells(IC50＞100 µmol·L-1).In addition,71 showed specific inhibitory effect on CDK9 kinase activity in vitro.Upon 1 µmol·L-1 71 treatment,CDK9 kinase activity was only(21.67±1.47)％,and in gastric cancer cells 71 inhibited CDK9 downstream protein p-ser2 expression in a concentration-dependent manner.Finally,molecular docking study showed that 71 could stably bind to the active site of CDK9 and had a high binding affinity.CONCLUSION This series of compounds have good anti-gastric cancer activity and are worth of further study.
维普
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