化学
吲哚试验
甲酰胺
对接(动物)
体外
立体化学
脚手架
激酶
体内
IC50型
酰胺
组合化学
结构-活动关系
铅化合物
生物化学
医学
生物医学工程
作者
Hongyu Hu,Jun Wu,Mingtao Ao,Xiaoping Zhou,Boqun Li,Zhenzhen Cui,Tong Wu,Li-Juan Wang,Yuhua Xue,Zhen Wu,Mei-Juan Fang
标识
DOI:10.1016/j.bioorg.2020.104064
摘要
In continuation of our previous work on the investigation of CDK9 inhibitors bearing indole moiety for the discovery of novel anticancer agents, novel methylenehydrazine-1-carboxamide derivatives with (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole scaffold were designed, synthesized, and evaluated for the CDK9 inhibitory activity and anticancer activity. Biological activity results demonstrated that most of these derivatives possessed good inhibitory on the kinase activity of CDK9 such as blocking its phosphorylation function and inhibiting HIV-1 transcription. Compound 12i was found to be the most potent CDK9 inhibitor and exhibited excellent anticancer activity against HepG2, A375, MCF-7, and A549, but low toxic on normal cells including HaCaT and MCF-10A. Further studies revealed that as a result of CDK9 inhibition and subsequent inhibition of phosphorylation at Serine 2 of the RNAPII CTD, the representative compound 12i dose-dependently increased cleaved PARP level, exerting its antiproliferative effect through induction of apoptosis in cancer cells. Finally, the molecular docking analysis implied that 12i had a good binding affinity with CDK9. In summary, 12i is a potent CDK9 inhibitor and can be considered as a good lead-candidate for developing potential anticancer drugs.
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