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

Teng Ai; Li Qiu; Jiashu Xie; Robert J Geraghty; Liqiang Chen

doi:10.1016/j.bmc.2015.12.035

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

Bioorg Med Chem. 2016 Feb 15;24(4):686-92. doi: 10.1016/j.bmc.2015.12.035. Epub 2015 Dec 23.

Authors

Teng Ai¹, Li Qiu¹, Jiashu Xie¹, Robert J Geraghty¹, Liqiang Chen²

Affiliations

¹ Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
² Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA. Electronic address: chenx462@umn.edu.

PMID: 26753813
DOI: 10.1016/j.bmc.2015.12.035

Abstract

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.

Keywords: Activity-based protein profiling; Benzothiophene; Cinnamic hydroxamic acid; Hepatitis C virus (HCV); Histone deacetylase; Hydroxamic acid; Matrix metalloproteinases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cinnamates / chemical synthesis
Cinnamates / chemistry
Cinnamates / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Hepacivirus / drug effects*
Hepacivirus / genetics
Hepacivirus / growth & development
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Microbial Sensitivity Tests
Molecular Probes / chemical synthesis
Molecular Probes / chemistry
Molecular Probes / pharmacology*
Molecular Structure
RNA, Viral / genetics
Structure-Activity Relationship
Virus Replication / drug effects
Virus Replication / genetics

Substances

Antiviral Agents
Cinnamates
Hydroxamic Acids
Molecular Probes
RNA, Viral