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.
authors.affiliation: School of Pharmacy, East China University of Science & Technology, Shanghai, 200237, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China.|Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450014, China.
authors.forename: Zhaoru
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmacy, East China University of Science & Technology, Shanghai, 200237, China.
authors.forename: Sufen
authors.initials: S
authors.lastname: Cao
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China.
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450014, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Jinpei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: School of Pharmacy, East China University of Science & Technology, Shanghai, 200237, China.|Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Shanghai, 201203, China.
authors.forename: Wenhu
authors.initials: W
authors.lastname: Duan
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D062105:Molecular Docking Simulation; D066244:Proton Magnetic Resonance Spectroscopy; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D011728:Pyridones; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 1,3-Diaryl-pyridone; Chan-Lam coupling; VEGFR-2 inhibitors; angiogenesis; anticancer agent