title: Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents.
abstract: A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (HT-29, H460, A549, MKN-45, and U87MG). Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines. Compounds 15a, 20a, 15b, 15c, 20d, and 16e were further examined for their inhibitory activity against c-Met kinase. The most promising compound 15a (c-Met half-maximal inhibitory concentration [IC50] = 2.15 nM) showed remarkable cytotoxicity against HT-29, H460, and A549 cell lines with IC50 values of 0.10 μM, 0.13 μM, and 0.05 μM, respectively, and thus it was 1.5- 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.
authors.forename: Shunguang
authors.initials: S
authors.lastname: Zhou
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: Huimin
authors.initials: H
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, Shenyang 110016, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: He
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: Yanan
authors.initials: Y
authors.lastname: Dou
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: Mingyan
authors.initials: M
authors.lastname: Jiang
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, Shenyang 110016, PR China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhao
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 / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011724:Pyridazines; D011804:Quinolines; C062482:pyridazine; D019859:Proto-Oncogene Proteins c-met
keywords: 4-Phenoxyquinoline derivatives; Antitumor activity; Synthesis; c-Met inhibitors