Discovery of 1,3-Diaryl-pyridones as Potent VEGFR-2 Inhibitors: Design, Synthesis, and Biological Evaluation

In this study, we described the design, synthesis, and biological evaluation of 1,3‐diaryl‐pyridones as vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibitors. The 1,3‐diaryl‐pyridones were synthesized via Chan‐Lam and Suzuki coupling reactions. Two representative compounds, 17 and 35h,...

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Published in:Chemical biology & drug design 2016-05, Vol.87 (5), p.694-703
Main Authors: Yan, Wei, Huang, Zhaoru, Wang, Zhengyu, Cao, Sufen, Tong, Linjiang, Zhang, Tao, Wang, Chen, Zhou, Lin, Ding, Jian, Luo, Cheng, Zhou, Jinpei, Xie, Hua, Duan, Wenhu
Format: Article
Language:English
Subjects:
1,3‐Diaryl‐pyridone
3-Diaryl-pyridone
angiogenesis
anticancer agent
Chan-Lam coupling
Drug Design
Drug Evaluation, Preclinical
Enzyme-Linked Immunosorbent Assay
Human Umbilical Vein Endothelial Cells
Humans
Molecular Docking Simulation
Proton Magnetic Resonance Spectroscopy
Pyridones - chemical synthesis
Pyridones - chemistry
Pyridones - pharmacology
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
VEGFR-2 inhibitors
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Summary:In this study, we described the design, synthesis, and biological evaluation of 1,3‐diaryl‐pyridones as vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibitors. The 1,3‐diaryl‐pyridones were synthesized via Chan‐Lam and Suzuki coupling reactions. Two representative compounds, 17 and 35h, displayed excellent enzymatic inhibitory activities, with IC50 values of 3.5 and 3.0 nm, respectively. Furthermore, compounds 17 and 35h blocked the tube formation and suppressed the VEGF‐induced phosphorylation of VEGFR‐2 and downstream extracellular signal‐regulated kinases (Erk) in human umbilical vein endothelial cells (HUVECs) at 10 nm concentration. The docking simulation showed that compound 17 bound well into the active site of VEGFR‐2 via two hydrogen bonds and hydrophobic interactions. Synthesis and biological evaluation of a novel series of 1,3‐diaryl‐pyridone derivatives as VEGFR‐2 inhibitors were described. Two representative compounds, 17 and 35h, exhibited excellent in vitro antiangiogenic activities. Docking simulation showed that compound 17 bound well into the active site of VEGFR‐2 with two hydrogen bonds and hydrophobic interactions.
ISSN:1747-0277
1747-0285
DOI:10.1111/cbdd.12703