当前位置： SCI文献检索 > BIOORGANIC CHEMISTRY期刊下所有文献 > Design, synthesis and biological evaluation of methylenehydrazine-1-carboxamide derivatives with (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole scaffold: Novel potential CDK9 inhibitors.

Design, synthesis and biological evaluation of methylenehydrazine-1-carboxamide derivatives with (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole scaffold: Novel potential CDK9 inhibitors.

Abstract：

: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.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Hu H,Wu J,Ao M,Zhou X,Li B,Cui Z,Wu T,Wang L,Xue Y,Wu Z,Fang M

doi

10.1016/j.bioorg.2020.104064

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

104064

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(20)31361-4

journal_volume

102

pub_type

杂志文章

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