title: Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: exploration of diverse hinge-binding fragments.
abstract: VEGFR-2 plays an essential role in angiogenesis and is an important target for cancer therapy. A series of biphenyl-aryl ureas were synthesized and evaluated as novel VEGFR-2 inhibitors. The pyridine, methylamine carbonyl pyridine and pivaloyl amide pyridine were introduced as novel hinge binding fragment. The majority of title compounds displayed potent VEGFR-2 inhibition. In particular, L1, L9, W14 and W15 exhibited significant enzymatic inhibitory activity with IC50 values of 0.36nM, 0.22nM, 0.15nM and 0.14nM. Compounds L1, L9 and W15 displayed potent antiproliferative activity against A549 and SMMC-7721 cells. SAR study suggested that incorporation of 3-trifluoromethyl and methylamine carbonyl on terminal pyridine could improve VEGFR-2 inhibitory activity. Molecular docking illustrated that urea moiety formed two critical hydrogen bonds with the DFG residues of VEGFR-2. The results indicated that these biphenyl-aryl ureas could serve as promising lead compounds for further optimization.
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Su
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
authors.forename: Ruili
authors.initials: R
authors.lastname: Shao
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D062105:Molecular Docking Simulation; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Biphenyl; Hinge region; Structural diversity; Urea; VEGFR-2 inhibitors