title: Discovery of novel anti-angiogenesis agents. Part 6: Multi-targeted RTK inhibitors.
abstract: Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, Tie-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/Tie-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, Tie-2, and EphB4. The representative compound (18a) displayed both potent multi-targeted RTK inhibition and considerable antiproliferative activities against human umbilical vein endothelial cells (EA.hy926). These results will contribute to the discovery of novel muti-targeted anti-angiogenesis agents.
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: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shan
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: Chuansheng
authors.initials: C
authors.lastname: Li
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: Ying
authors.initials: Y
authors.lastname: Sun
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: Lisha
authors.initials: L
authors.lastname: Li
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. Electronic address: zhj8623@xjtu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008314:Malonates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013890:Thiourea / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D008314:Malonates; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D013890:Thiourea; C008314:malonamide
keywords: Anti-angiogenesis agents; Diaryl malonamide; Diaryl thiourea; Multi-targeted; RTK inhibitors