title: Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK.
abstract: Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.
authors: School of Science, Anhui Agricultural University, Hefei 230036, PR China; School of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China.
authors: Xian-Hai
authors: XH
authors: Lv
authors: School of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China.
authors: Zi-Li
authors: ZL
authors: Ren
authors: School of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China.
authors: Ben-Guo
authors: BG
authors: Zhou
authors: School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China.
authors: Qing-Shan
authors: QS
authors: Li
authors: School of Science, Anhui Agricultural University, Hefei 230036, PR China.
authors: Ming-Jie
authors: MJ
authors: Chu
authors: School of Science, Anhui Agricultural University, Hefei 230036, PR China.
authors: Dao-Hong
authors: DH
authors: Liu
authors: School of Science, Anhui Agricultural University, Hefei 230036, PR China.
authors: Kai
authors: K
authors: Mo
authors: School of Science, Anhui Agricultural University, Hefei 230036, PR China.
authors: Li-Song
authors: LS
authors: Zhang
authors: School of Science, Anhui Agricultural University, Hefei 230036, PR China.
authors: Xiao-Kang
authors: XK
authors: Yao
authors: School of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China. Electronic address: haiquncao@163.com.
authors: Hai-Qun
authors: HQ
authors: Cao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D048369:MAP Kinase Kinase 1; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C010574:biphenyl
keywords: Anti-cancer activity; Inhibitors; MEK; Molecular docking; Pyrazole; QSAR