Studies of benzamide- and thiol-based histone deacetylase inhibitors in models of oxidative-stress-induced neuronal death: Identification of some HDAC3-selective inhibitors

Yufeng Chen, Rong He, Yihua Chen, Melissa A. D'Annibale, Brett Langley, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)842-852
Number of pages11
JournalChemMedChem
Volume4
Issue number5
DOIs
StatePublished - May 11 2009

Keywords

  • Benzamides
  • HDAC inhibitors
  • Neurological agents
  • Oxidative stress
  • Prodrugs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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