title: Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety.
abstract: A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50=1.21/2.15nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure-activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity.
authors.affiliation: School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: tangqidongcn@126.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhai
authors.affiliation: School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Tu
authors.affiliation: School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China.
authors.forename: Linxiao
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China.
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wang
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, PR China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China. Electronic address: zhengpw@126.com.
authors.forename: Pengwu
authors.initials: P
authors.lastname: Zheng
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D054879:Halogenation; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met
keywords: 2-Oxo-4-chloro-1,2-dihydroquinoline; Antiproliferative activity; Quinoline derivatives; Synthesis; c-Met