title: Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors.
abstract: A series of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety were synthesized and evaluated for their in vitro cytotoxic activity against four cancer cell lines (HT-29, H460, A549 and MKN-45). Most of the compounds exhibited moderate-to-significant cytotoxicity. Compounds 33, 37, 39, 44, 46, 47, 53, 55, 61, 64 and 66 were further examined for their inhibitory activity against c-Met kinase. The most promising compound 47 (with c-Met IC50 value of 1.57 nM) showed remarkable cytotoxicity against HT-29, H460, A549 and MKN-45 cell lines with IC50 values of 0.08 μM, 0.14 μM, 0.11 μM and 0.031 μM, respectively, and thus it was 1.1- to 2.3- fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China; College of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 10036, PR China.
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Minhua
authors.initials: M
authors.lastname: Nie
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Jinxing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: lyjpharm@126.com.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D014230:Triazoles; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: 4-Phenoxyquinoline derivatives; Antitumor activity; Synthesis; c-Met inhibitors