title: Biphenyl derivatives incorporating urea unit as novel VEGFR-2 inhibitors: design, synthesis and biological evaluation.
abstract: A series of novel biphenyl urea derivates were synthesized and investigated for their potential to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2). In particular, A7, B3 and B4 displayed significant enzymatic inhibitory activities, with IC₅₀ values of 4.06, 4.55 and 5.26 nM. Compound A7 exhibited potent antiproliferative activity on several cell lines. SAR study suggested that the introduction of methyl at ortho-position of the biphenyl urea and tertiary amine moiety could improve VEGFR-2 inhibitory activity and antitumor effects. Molecular docking indicated that the urea moiety formed four hydrogen bonds with DFG residue. These biphenyl ureas could serve as promising lead compounds for further optimization.
authors: School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors: Chen
authors: C
authors: Wang
authors: School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors: Hongping
authors: H
authors: Gao
authors: School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors: Jinyun
authors: J
authors: Dong
authors: School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors: Yanmin
authors: Y
authors: Zhang
authors: School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors: Ping
authors: P
authors: Su
authors: School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors: Yaling
authors: Y
authors: Shi
authors: School of Medicine, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.
authors: Jie
authors: J
authors: Zhang
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry; D049109:Cell Proliferation; D006801:Humans; D008958:Models, Molecular; D009389:Neovascularization, Pathologic; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D014508:Urea; D040301:Vascular Endothelial Growth Factor Receptor-2; C010574:biphenyl
keywords: Angiogenesis; Biphenyl scaffold; Urea moiety; VEGFR-2 inhibitor