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

Wei Yan, Zhaoru Huang, Zhengyu Wang, Sufen Cao, Linjiang Tong, Tao Zhang, Chen Wang, Lin Zhou, Jian Ding, Cheng Luo, Jinpei Zhou, Hua Xie, Wenhu Duan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)694-703
Number of pages10
JournalChemical Biology and Drug Design
Volume87
Issue number5
DOIs
StatePublished - May 1 2016
Externally publishedYes

Keywords

  • 1,3-Diaryl-pyridone
  • angiogenesis
  • anticancer agent
  • Chan-Lam coupling
  • VEGFR-2 inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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