title: Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors.
abstract: A novel series of N(1)-(3-fluoro-4-(6,7-disubstituted-quinolin-4-yloxy)phenyl)-N(4)-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50=1.4nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China.
authors.forename: Baohui
authors.initials: B
authors.lastname: Qi
authors.forename: Bin
authors.initials: B
authors.lastname: Mi
authors.forename: Xin
authors.initials: X
authors.lastname: Zhai
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Xu
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhang
authors.forename: Zeru
authors.initials: Z
authors.lastname: Tian
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D012663:Semicarbazides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D012664:Semicarbazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C587053:N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-N4-(2,4-difluorobenzylidene)semicarbazide; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D012663:Semicarbazides; D012664:Semicarbazones; D019859:Proto-Oncogene Proteins c-met
keywords: Anti-tumor; Kinase inhibitor; Quinoline; Semicarbazone; c-Met