Design, synthesis, biological evaluation and molecular modeling of novel 1H-pyrrolo[2,3-b]pyridine derivatives as potential anti-tumor agents

被引:22
作者
Wang, Ruifeng [1 ]
Chen, Yixuan [1 ]
Yang, Bowen [1 ]
Yu, Sijia [1 ]
Zhao, Xiangxin [1 ]
Zhang, Cai [2 ]
Hao, Chenzhou [1 ]
Zhao, Dongmei [1 ]
Cheng, Maosheng [1 ]
机构
[1] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Key Lab Struct Based Drug Design & Discovery, Minist Educ, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China
[2] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China
关键词
MELK inhibitor; 1H-pyrrolo[2,3-b]pyridine; Structure-activity relationship; Biological evaluation; ZIPPER KINASE MELK; DISCOVERY; INHIBITORS; PROLIFERATION; DOCKING;
D O I
10.1016/j.bioorg.2019.103474
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A class of 3-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were designed, synthesized and evaluated for their in vitro biological activities against maternal embryonic leucine zipper kinase (MELK). Among these derivatives, the optimized compound 16h exhibited potent enzyme inhibition (IC50, = 32 nM) and excellent anti-pro-liferative effect with IC50, values from 0.109 mu M to 0.245 mu M on A549, MDA-MB-231 and MCF-7 cell lines. The results of flow cytometry indicated that 16h promoted apoptosis of A549 cells in a dose-dependent manner and effectively arrested A549 cells in the G0/G1 phase. Further investigation indicated that compound 16h potently suppressed the migration of A549 cells, had moderate stability in rat liver microsomes and showed moderate inhibitory activity against various subtypes of human cytochrome P450. However, compound 16h is a multi-target kinase inhibitor and recently several studies reported MELK expression is not required for cancer growth, suggesting that compound 16h suppressed the proliferation and migration of cancer cells should through an off-target mechanism. Collectively, compound 16h has the potential to serve as a new lead compound for further anticancer drug discovery.
引用
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页数:12
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