title: Chiral mercaptoacetamides display enantioselective inhibition of histone deacetylase 6 and exhibit neuroprotection in cortical neuron models of oxidative stress.
abstract: Mercaptoacetamide-based ligands have been designed as a new class of histone deacetylase (HDAC) inhibitors for possible use in the treatment of neurodegenerative diseases. The thiol group of these compounds provides a key binding element for interaction with the catalytic zinc ion, and thus differs from the more typically employed hydroxamic acid based zinc binding groups. Herein we disclose the chemistry and biology of some substituted mercaptoacetamides with the intention of increasing HDAC6 isoform selectivity while maintaining potency similar to their hydroxamic acid analogues. The introduction of a stereocenter α to the thiol group was found to have a considerable impact on HDAC inhibitor potency. These new compounds were also profiled for their therapeutic potential in an in vitro model of stress-induced neuronal injury and were found to act as nontoxic neuroprotective agents.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612-7211, USA.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kalin
authors.forename: Hankun
authors.initials: H
authors.lastname: Zhang
authors.forename: Sophie
authors.initials: S
authors.lastname: Gaudrel-Grosay
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D019281:Dimerization; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000081:Acetamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D020033:Protein Isoforms; D013438:Sulfhydryl Compounds; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases