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 |
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| Institution: | 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China;2. Shenyang J & Health Bio-technic Development, Shenyang 110016, PR China;1. School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China;2. Fushun Center for Drug Control, Fushun 113000, PR China;3. Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China;1. Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China;2. College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang Province, China |
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| 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 = 1.63 nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055 μM, 0.071 μM, 0.13 μM, and 0.43 μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively. |
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| Keywords: | c-Met Antitumor activity 4-Phenoxyquinoline derivatives |
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