title: Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors.
abstract: A series of 4-(2-fluorophenoxy)quinoline derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five cancer cell lines (A549, H460, HT-29, MKN-45, and U87MG). Most compounds showed weak to excellent antiproliferative activity. The most promising analog, 40 (c-Met IC50 = 1.86 nM), displayed 1.3-, 6.8-, 1.5-, 3.5-fold increase against HT-29, H460, A549 and U87MG cell lines, respectively, compared with Foretinib. An analysis of structure-activity relationships revealed that an acylhydrazone scaffold with an unsubstituted sp(2) hybridized carbon adjacent to the 4-CF3 phenyl ring is favorable for antitumor activity.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China.
authors.forename: Weike
authors.initials: W
authors.lastname: Liao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ji
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Shenyang J & Health Bio-technic Development, Shenyang 110016, PR China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Ren
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China.
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, PR China.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China. Electronic address: gongpinggp@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China. Electronic address: suntiemin@126.com.
authors.forename: Tiemin
authors.initials: T
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D006835:Hydrazones / Q000032:analysis*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D047428:Protein Kinase Inhibitors; D015363:Quinolones; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: Acylhydrazone; Quinoline derivatives; Synthesis; c-Met