Studies of Benzamide‐ and Thiol‐Based Histone Deacetylase Inhibitors in Models of Oxidative‐Stress‐Induced Neuronal Death: Identification of Some HDAC3‐Selective Inhibitors

Abstract Less stress: We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. Novel benzamide‐based ligands selectively inhibit HDAC3 but provide no neuroprotection in the HCA–cortical neuron model of oxidative stress. magnified image We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. This study reveals that none of the benzamide‐based HDAC inhibitors (HDACIs) provides any neuroprotection whatsoever, in distinct contrast to HDACIs that contain other ZBGs. Some of the sulfur‐containing HDACIs, namely the thiols, thioesters, and disulfides present modest neuroprotective activity but show toxicity at higher concentrations. Taken together, these data demonstrate that the HDAC6‐selective mercaptoacetamides that were reported previously provide the best protection in the homocysteic acid model of oxidative stress, thus further supporting their study in animal models of neurodegenerative diseases.