In this presentation, we describe the design, synthesis,and biological evaluation of active and selective HDAC3 and HDAC8 diazide isoxazole-basedand pyrazole-based probes suitable for photolabeling experiments in cells. Wealso performed a closely related small SAR study focused on a novelpyrazole-based scaffold and optimized the synthetic procedures for gram scalesynthesis. Both the isoxazole- and pyrazole-based probes exhibit excellent lowdouble digit nanomolar inhibitory activity against HDAC3 and HDAC8,respectively. The cell-based experiments show that these probes are cellpermeable and exert an anti-proliferative activity towards HepG2, Hela, andSH-SY5Y cell lines, and neuroprotective activity in SH-SY5Y cell lines at micromolar concentrations. The presence of an azide ora diazide group does not interfere with the neuroprotection properties, orenhance cellular cytotoxicity, or affect cell permeability, making these probesexcellent candidates for cell-based photolabeling experiments.

Design, synthesis, and biological evaluation of novel diazide-containing pyrazole- and isoxazole-based HDAC probes

241st National Meeting (2011)

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