title: Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents.
abstract: A series of 2-(1H-imidazol-2-yl) pyridine derivatives (CLW01-CLW31) have been designed and synthesized, and they were screened for BRAF kinase inhibitory activity. Besides, their biological activities were evaluated in vitro and in vivo. All the compounds were reported for the first time, and compounds CLW14 and CLW27 displayed the most potent antiproliferative activity against cell line A375 in vitro, with IC50 values of 4.26 and 2.93 μM, respectively, which were comparable with the positive control Sorafenib. Those two compounds were further evaluated for the in vivo efficacy using an A375 xenograft nude mice model. The results showed that the growth of A375 cancer cells xenografts was suppressed by factors of 35.68% and 42.50% (percent tumor growth inhibition values) after intragastric (ig) administration of compound CLW14 and CLW27 at concentration of 50 mg/kg. Thus they may be promising lead compounds to be developed as an alternative for current Sorafenib therapy.
authors.affiliation: Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors.forename: Bo-Tao
authors.initials: BT
authors.lastname: Xin
authors.affiliation: Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China. Electronic address: stephanie055@163.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077157:Sorafenib; D013329:Structure-Activity Relationship
chemical_list: C000601654:2-(1H-imidazol-2-yl)pyridine; D000970:Antineoplastic Agents; D007093:Imidazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf
keywords: Antiproliferative activity; BRAF kinase; Cancer cell; In vivo efficacy; Sorafenib