Abstract
A unique series of biologically active chemical probes that selectively inhibit NF-kappaB activation induced by protein kinase C (PKC) pathway activators have been identified through a cell-based phenotypic reporter gene assay. These 2-aminobenzimidazoles represent initial chemical tools to be used in gaining further understanding on the cellular mechanisms driven by B and T cell antigen receptors. Starting from the founding member of this chemical series 1a (notated in PubChem as CID-2858522), we report the chemical synthesis, SAR studies, and pharmacological profiling of this pathway-selective inhibitor of NF-kappaB activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Cell Line
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Cell Membrane Permeability
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Genes, Reporter
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Humans
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Hydrophobic and Hydrophilic Interactions
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Interleukin-2 / biosynthesis
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Interleukin-8 / biosynthesis
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Male
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Mice
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Microsomes, Liver / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / genetics
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NF-kappa B / physiology
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Protein Kinase C / physiology*
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Receptors, Antigen, B-Cell / physiology
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Receptors, Antigen, T-Cell / physiology
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Signal Transduction
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Small Molecule Libraries
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Structure-Activity Relationship
Substances
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1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(2-((3-hydroxypropyl)amino)-5,6-dimethyl-1H-benzo(d)imidazol-1-yl)ethanone
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Benzimidazoles
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Interleukin-2
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Interleukin-8
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NF-kappa B
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Receptors, Antigen, B-Cell
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Receptors, Antigen, T-Cell
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Small Molecule Libraries
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Protein Kinase C