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
复制标题
具有 (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole 支架的亚甲基肼-1-甲酰胺衍生物的设计、合成和生物学评价：新型潜在 CDK9 抑制剂
DOI：
10.1016/j.bioorg.2020.104064
复制
发表时间：
2020-09-01
影响因子：
5.1
通讯作者：
Fang, Meijuan
中科院分区：
文献类型：
--
作者：
Hu, Hongyu;Wu, Jun;Fang, Meijuan
为了继续我们以前的工作，研究带有吲哚部分的CDK 9抑制剂以发现新的抗癌药物，设计、合成了具有（5-（（4-（吡啶3-基）嘧啶-2-基）氨基）-1H-吲哚骨架的新型亚甲基肼-1-甲酰胺衍生物，并评价了CDK 9抑制活性和抗癌活性。生物活性研究结果表明，这些衍生物对CDK 9的激酶活性具有较好的抑制作用，如阻断其磷酸化功能和抑制HIV-1的转录。发现化合物12 i是最有效的CDK 9抑制剂，并对HepG 2、A375、MCF-7和A549表现出优异的抗癌活性，但对正常细胞（包括HaCaT和MCF-10A）的毒性较低。进一步的研究表明，作为抑制CDK 9和随后抑制RNAPII CTD的丝氨酸2处磷酸化的结果，代表性化合物12 i剂量依赖性地增加裂解的PARP水平，通过诱导癌细胞中的细胞凋亡发挥其抗增殖作用。最后，分子对接分析表明12 i与CDK 9具有良好的结合亲和力。总之，12 i是一种有效的CDK 9抑制剂，可以被认为是开发潜在抗癌药物的良好候选药物。
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-(pyridin3-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.