title: Design, modification and 3D QSAR studies of novel 2,3-dihydrobenzo[b][1,4]dioxin-containing 4,5-dihydro-1H-pyrazole derivatives as inhibitors of B-Raf kinase.
abstract: Two series of novel 2,3-dihydrobenzo[b][1,4]dioxin-containing 4,5-dihydro-1H-pyrazole derivatives C1-C15 and D1-D15 have been synthesized and evaluated for their B-Raf inhibitory and anti-proliferation activities. Compound C14 ((3-(4-bromophenyl)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone) showed the most potent biological activity against B-Raf(V600E) (IC(50) = 0.11 μM) and WM266.4 human melanoma cell line (GI(50) = 0.58 μM), being comparable with the positive control Erlotinib and more potent than our previous best compound, while D10 ((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(5-(3-fluorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone) performed the best in the D series (IC(50) = 1.70 μM; GI(50) = 1.45 μM). The docking simulation was performed to analyze the probable binding models and poses and the QSAR model was built for reasonable design of B-Raf inhibitors in future. The introduction of 2,3-dihydrobenzo[b][1,4]dioxin structure reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Yu-Shun
authors.initials: YS
authors.lastname: Yang
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Li
authors.forename: Shuai
authors.initials: S
authors.lastname: Sun
authors.forename: Yan-Bin
authors.initials: YB
authors.lastname: Zhang
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Tang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004147:Dioxins / Q000737:chemistry*; D015195:Drug Design; D000069347:Erlotinib Hydrochloride; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: C578257:(2,3-dihydrobenzo(b)(1,4)dioxin-2-yl)(5-(3-fluorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone; C521468:2,3-dihydrobenzo(1,4)dioxin; D004146:Dioxanes; D004147:Dioxins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; C031280:pyrazole; D000069347:Erlotinib Hydrochloride; D048493:Proto-Oncogene Proteins B-raf