Abstract
The design, synthesis, docking, and biological evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) experiments in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, respectively. The pyrazole-based probe 3f appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC(50) of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors 2b, 3a, 3c, and 3f exerted the antiproliferative and neuroprotective activities at micromolar concentrations through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.
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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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Azides / chemical synthesis*
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Azides / chemistry
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Azides / pharmacology
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Cell Line, Tumor
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Cell Membrane Permeability
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Drug Design
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Drug Screening Assays, Antitumor
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Histone Deacetylase Inhibitors / chemical synthesis*
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / chemistry*
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Histone Deacetylases / metabolism
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology
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Matrix Metalloproteinase Inhibitors
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Matrix Metalloproteinases / chemistry
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Models, Molecular*
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Photoaffinity Labels / chemical synthesis*
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Photoaffinity Labels / chemistry
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Photoaffinity Labels / pharmacology
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Protein Binding
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Repressor Proteins / chemistry
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Repressor Proteins / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Azides
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Isoxazoles
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Matrix Metalloproteinase Inhibitors
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Neuroprotective Agents
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Photoaffinity Labels
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Pyrazoles
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Repressor Proteins
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octanedioic acid (1-(3-azido-5-azidomethylbenzyl)-1H-pyrazol-4-yl)amide hydroxyamide
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Matrix Metalloproteinases
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HDAC8 protein, human
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Histone Deacetylases
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histone deacetylase 3