Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes.
Article Details
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Neelarapu R, Holzle DL, Velaparthi S, Bai H, Brunsteiner M, Blond SY, Petukhov PA
Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes.
J Med Chem. 2011 Jul 14;54(13):4350-64. doi: 10.1021/jm2001025. Epub 2011 Jun 2.
- PubMed ID
- 21548582 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Trichostatin A Histone deacetylase 7 IC 50 (nM) 139 N/A N/A Details Vorinostat Histone deacetylase 1 IC 50 (nM) 22.37 N/A N/A Details Vorinostat Histone deacetylase 2 IC 50 (nM) 100 N/A N/A Details Vorinostat Histone deacetylase 3 IC 50 (nM) 27 N/A N/A Details