title: Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives as selective c-Met inhibitors.
abstract: Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC50]=1.1nM) demonstrated high selectivity and remarkable cytotoxicity against HT-29, MKN-45 and A549 cells with IC50values of 0.08, 0.22 and 0.07μM, which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity relationships as well as molecular docking disclosed that 1H-imidazole-4-carboxamido as a linker was of great importance for the antitumor activity.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Sijia
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Shuancheng
authors.initials: S
authors.lastname: Xi
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Tongfei
authors.initials: T
authors.lastname: Jing
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zhaixin_syphu@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhai
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met
keywords: 6,7-Disubstituted-4-(2-fluorophenoxy)quinolines; Antitumor activity; Molecular docking; Synthesis; c-Met