title: Design and synthesis of novel substituted naphthyridines as potential c-Met kinase inhibitors based on MK-2461.
abstract: Two series of novel 1,5-naphthyridine and 1,6-naphthyridine derivatives were designed and synthesized based on the c-Met kinase inhibitor MK-2461 under the guidance of scaffold hopping strategy. All were tested on c-Met kinase and in vitro anti-tumor activities against Hela and A549 cell lines. The results indicated that 1,6-naphthyridine was a more promising c-Met inhibitory structure core compared with 1,5-naphthyridine. Among them, 26b and 26c showed the best enzymic and cytotoxic activities. The western blot experiments implied that the cytotoxic activity of 26c might be partially through suppressing the phosphorylation of c-Met kinase.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Wu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address: hsx@sioc.ac.cn.
authors.forename: Shao-Xu
authors.initials: SX
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: wangyang@shmu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001567:Benzocycloheptenes / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: C561052:5H-benzo(4,5)cyclohepta(1,2-b)pyridin-5-one; D000970:Antineoplastic Agents; D001567:Benzocycloheptenes; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D019859:Proto-Oncogene Proteins c-met
keywords: 1,5-Naphthyridine derivatives; 1,6-Naphthyridine derivatives; Cytotoxic activity; MK-2461; c-Met kinase inhibitors