title: Design, synthesis and biological evaluation of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors.
abstract: A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50=1.63nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055μM, 0.071μM, 0.13μM, and 0.43μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.
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: Zijian
authors.initials: Z
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: Rui
authors.initials: R
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: Ruiming
authors.initials: R
authors.lastname: Guo
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: 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, 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; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C000593981:N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: 2-Phenylphthalazin-1(2H)-one; 4-Phenoxyquinoline derivatives; Antitumor activity; c-Met