title: Synthesis, biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors.
abstract: A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 μM for MCF-7 and IC(50) = 0.45 μM for WM266.5, IC(50) = 0.22 μM for BRAF(V600E), 3m: IC(50) = 0.97 μM for MCF-7 and IC(50) = 0.72 μM for WM266.5, IC(50) = 0.46 μM for BRAF(V600E), which were comparable with the positive control Erlotinib.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Sun
authors.forename: Zhong-Chang
authors.initials: ZC
authors.lastname: Wang
authors.forename: Yu-Shun
authors.initials: YS
authors.lastname: Yang
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Gong
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002733:Chlorophenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C578261:1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone; C578260:1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone; D000970:Antineoplastic Agents; D002733:Chlorophenols; D010636:Phenols; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf