title: Synthesis and biological evaluation of 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazone scaffolds as selective c-Met inhibitors.
abstract: Novel quinoline derivatives bearing acyclic semicarbazones were prepared and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for their c-Met kinase inhibitory activity and their cytotoxicity against the cell lines HT-29, MKN-45, and MDA-MB-231 in vitro. Several potent compounds were further evaluated against A549 cells. Most compounds displayed moderate to excellent activity, and the structure-activity relationship studies identified the most promising compound 35 as a selective c-Met kinase inhibitor (IC50  = 4.3 nM). Compound 35 showed a 3.5- and 18.8-fold increase in cytotoxicity in vitro against HT-29 and A549 cells, respectively, compared to that of foretinib. Poor off-target effects of compound 35 were further confirmed by the antiproliferative activity against the c-Met inhibition less sensitive MDA-MB-231 cell line (IC50  = 0.77 µM).
authors.affiliation: Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China.
authors.forename: Baohui
authors.initials: B
authors.lastname: Qi
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tao
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Jinying
authors.initials: J
authors.lastname: Bai
authors.forename: Yandan
authors.initials: Y
authors.lastname: Shi
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012664:Semicarbazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C544831:GSK 1363089; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D012664:Semicarbazones; D019859:Proto-Oncogene Proteins c-met
keywords: Kinase inhibitors; Quinoline; SAR; Semicarbazone; c-Met