title: Design, synthesis and biological evaluation of novel benzo-α-pyrone containing piperazine derivatives as potential BRAFV600Einhibitors.
abstract: The increasingly acquired resistance to vemurafenib and side effects of known inhibitors motivate the search for new and more effective anti-melanoma drugs. In this Letter, virtual screening and scaffold growth were combined together to achieve new molecules as BRAFV600Einhibitors. Along with docking simulation, a primary screen in vitro was performed to filter the modifications for the lead compound, which was then substituted, synthesized and evaluated for their inhibitory activity against BRAFV600Eand several melanoma cell lines. Out of the obtained compounds, derivative 3l was identified as a potent BRAFV600Einhibitor and exerted an anticancer effect through BRAFV600Einhibition. The following biological evaluation assays confirmed that 3l could induce cell apoptosis and marked DNA fragmentation. Furthermore, 3l could arrest the cell cycle at the G0/G1 phase in melanoma cells. The docking simulation displayed that 3l could tightly bind with the crystal structure of BRAFV600Eat the active site. Overall, the biological profile of 3l suggests that this compound may be developed as a potential anticancer agent.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Long-Wang
authors.initials: LW
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Ze-Feng
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Jiangsu Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing 210000, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Ruo-Jun
authors.initials: RJ
authors.lastname: Man
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Yan-Dong
authors.initials: YD
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Yuan-Heng
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Bao-Zhong
authors.initials: BZ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Zhong-Chang
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D011753:Pyrones; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF(V600E); Benzo-α-pyrone; Docking simulation; Melanoma; Virtual screening