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

doi:10.1111/cbdd.12703

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 journal › Article › peer-review

5 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 language	English (US)
Pages (from-to)	694-703
Number of pages	10
Journal	Chemical Biology and Drug Design
Volume	87
Issue number	5
DOIs	https://doi.org/10.1111/cbdd.12703
State	Published - May 1 2016
Externally published	Yes

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

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.",

keywords = "1,3-Diaryl-pyridone, angiogenesis, anticancer agent, Chan-Lam coupling, VEGFR-2 inhibitors",

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

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year = "2016",

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day = "1",

doi = "10.1111/cbdd.12703",

language = "English (US)",

volume = "87",

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TY - JOUR

T1 - Discovery of 1,3-Diaryl-pyridones as Potent VEGFR-2 Inhibitors

T2 - Design, Synthesis, and Biological Evaluation

AU - Yan, Wei

AU - Huang, Zhaoru

AU - Wang, Zhengyu

AU - Cao, Sufen

AU - Tong, Linjiang

AU - Zhang, Tao

AU - Wang, Chen

AU - Zhou, Lin

AU - Ding, Jian

AU - Luo, Cheng

AU - Zhou, Jinpei

AU - Xie, Hua

AU - Duan, Wenhu

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - 1,3-Diaryl-pyridone

KW - angiogenesis

KW - anticancer agent

KW - Chan-Lam coupling

KW - VEGFR-2 inhibitors

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SN - 1747-0277

VL - 87

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EP - 703

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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