title: Design, synthesis, and biological evaluation of 3-vinyl-quinoxalin-2(1H)-one derivatives as novel antitumor inhibitors of FGFR1.
abstract: FGFR1 is well known as a molecular target in anticancer drug design. TKI258 plays an important role in RTK inhibitors. Utilizing TKI258 as a lead compound that contains a quinazolinone nucleus, we synthesized four series of 3-vinyl-quinoxalin-2(1H)-one derivatives, a total of 27 compounds. We further evaluated these compounds for FGFR1 inhibition ability as well as cytotoxicity against four cancer cell lines (H460, B16-F10, Hela229, and Hct116) in vitro. Some compounds displayed good-to-excellent potency against the four tested cancer cell lines compared with TKI258. Structure-activity relationship analyses indicated that small substituents at the side chain of the 3-vinyl-quinoxalin-2(1H)-one were more effective than large substituents. Lastly, we used molecular docking to obtain further insight into the interactions between the compounds and FGFR1.
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Shen
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Leping
authors.initials: L
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Jinsan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Faqing
authors.initials: F
authors.lastname: Ye
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001686:Biological Phenomena; D045744:Cell Line, Tumor; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000617754:3-vinyl-quinoxalin-2(1H)-one; C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D011810:Quinoxalines; D014753:Vinyl Compounds; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: FGFR1; antitumor activity; kinase inhibitor; quinoxaline; synthesis