Design, Synthesis and Biological Evaluation of Uracil Derivatives as Novel VEGFR-2 Inhibitors

被引:3
|
作者
Liang, Jingwei [1 ]
Li, Xinyang [1 ]
Yang, Su [1 ]
He, Xin [1 ]
Wang, Mingyang [1 ]
Meng, Fanhao [1 ]
机构
[1] China Med Univ, Sch Pharm, Shenyang 110122, Liaoning, Peoples R China
基金
中国国家自然科学基金;
关键词
VEGFR-2; inhibitor; uracil; virtual screening; Acyl aromatic hydrazine; cancer angiogenesis; ATP-competitive inhibitors; DRUG DESIGN; KINASE; CANCER; ANGIOGENESIS; GROWTH; DISCOVERY; DOCKING; AGENTS; CELLS;
D O I
10.2174/1381612824666180130123430
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Backgound: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. Type I inhibitors constitute the major ATP-competitive inhibitors and recognize mainly the active conformation of VEGFR-2. Meanwhile, type II inhibitors recognize the inactive DFG (Asp-Phe-Gly)-out conformation of VEGFR-2, which was a more promising approach for drug intervention. Methods: According to the lead compound of uracil skeleton, being screened out by structure-based virtual screening, a series of uracil derivatives were designed and synthesized. Results: The inhibitory activities were investigated against VEGFR-2 kinase in vitro. The results turned out that series A performed moderate inhibitory activities, especially compound A4 exhibited the most potent inhibitory activity (IC50 = 0.029 mu M). Conclusion: The lead compound was screened out by structure-based pharmacophore models, then two series of uracil derivatives were synthesized according to it and evaluated for their inhibitory activities against VEGFR-2. In this study, not only a potential inhibitor has been discovered, it also demonstrates the feasibility of structure-based virtual screening method for drug discovery.
引用
收藏
页码:734 / 740
页数:7
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