title: Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates as potent VEGFR-2 kinase inhibitors.
abstract: Inhibition of VEGFR-2 kinase has been highlighted as one of the well-defined strategies to suppress tumor growth via blockade of angiogenesis. Guided by the principles of bioisosteric replacement and pharmacophoric fragment migration, a series of novel quinoxalinone derivates were designed, synthesized and evaluated for their VEGFR-2 inhibitory potencies. Among them, compounds 7c, 8b, 8c, 8e and 10b displayed antiangiogenic abilities via the in vitro tube formation assay (cellular level) and ex vivo rat aortic ring assay (tissue level) at a low concentration (0.1 μM). By means of in vivo zebrafish embryo model, two (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates 8c and 8e showed significant antiangiogenesis effects, suggesting they have potentials to be developed into antiangiogenesis agents via further structural optimization. Moreover, these two compounds also demonstrated potent inhibition toward VEGFR-2 and B-raf kinases in a low concentration (1 μM). A possible interpretation of our evaluation result has been presented by a molecular docking study by docking representative compound 8c with VEGFR-2.
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Shandong University, Ji'nan, Shandong 250012, PR China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Shi
authors.affiliation: School of Medicine and Pharmacy, Ocean University of China, Qingdao 266100, PR China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Criminal Science and Technology, Ji'nan Public Security Bureau, Ji'nan 250100, PR China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Wu
authors.affiliation: School of Medicine, Shandong University, Ji'nan 250012, PR China.
authors.forename: Junya
authors.initials: J
authors.lastname: Cao
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Shandong University, Ji'nan, Shandong 250012, PR China.
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Chemistry, Texas A & M University, College Station, TX 77842, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address: tjulx2004@sdu.edu.cn.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Activity evaluation; Antiangiogenesis; Pyridyl motif; Quinoxalinone derivates; VEGFR-2 inhibitor