Design and synthesis of an activity-based protein profiling probe derived from cinnamic hydroxamic acid

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• 作者：Teng Ai ; Li Qiu ; Jiashu Xie ; Robert J. Geraghty ; Liqiang Chen ; ^{chenx462@umn.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ABPP ; activity-based protein profiling ; ADME ; absorption ; distribution ; metabolism ; and excretion ; DAAs ; direct-acting antivirals ; DPBS ; Dulbecco&rsquo ; s phosphate-buffered saline ; HCV ; hepatitis C virus ; HDACs ; histone deacetylases ; HTAs ; host-targeting antivirals ; 2mA ; 2&prime ; -C-methyl adenosine ; MMPs ; matrix metalloproteinases ; NADPH ; nicotinamide adenine dinucleotide phosphate ; RT-qPCR ; reverse transcription and quantitative PCR ; SAR ; structure&ndash ; activity relationship ; SOC ; standard of
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：24
• 期：4
• 页码：686-692
• 全文大小：787 K

文摘

In our continued effort to discover new anti-hepatitis C virus (HCV) agents, we validated the anti-replicon activity of compound 1, a potent and selective anti-HCV hydroxamic acid recently reported by us. Generally favorable physicochemical and in vitro absorption, distribution, metabolism, and excretion (ADME) properties exhibited by 1 made it an ideal parent compound from which activity-based protein profiling (ABPP) probe 3 was designed and synthesized. Evaluation of probe 3 revealed that it possessed necessary anti-HCV activity and selectivity. Therefore, we have successfully obtained compound 3 as a suitable ABPP probe to identify potential molecular targets of compound 1. Probe 3 and its improved analogs are expected to join a growing list of ABPP probes that have made important contributions to not only the studies of biochemical and cellular functions but also discovery of selective inhibitors of protein targets.