Stereoselective HDAC inhibition from cysteine-derived zinc-binding groups

Kyle V. Butler, Rong He, Kathryn McLaughlin, Giulio Vistoli, Brett Langley, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

A series of small-molecule histone deacetylase (HDAC) inhibitors, which feature zinc binding groups derived from cysteine, were synthesized. These inhibitors were tested against multiple HDAC isoforms, and the most potent, compound 10, was determined to have IC50 values below 1 μM. The compounds were also tested in a cellular assay of oxidative stress-induced neurodegeneration. Many of the inhibitors gave near-complete protection against cell death at 10 μM without the neurotoxicity seen with hydroxamic acid-based inhibitors, and were far more neuroprotective than HDAC inhibitors currently in clinical trials. Both enantiomers of cysteine were used in the synthesis of a variety of novel zinc-binding groups (ZBGs). Derivatives of L-cysteine were active in the HDAC inhibition assays, while the derivatives of D-cysteine were inactive. Notably, the finding that both the D- and L-cysteine derivatives were active in the neuroprotection assays suggests that multiple mechanisms are working to protect the neurons from cell death. Molecular modeling was employed to investigate the differences in inhibitory activity between the HDAC inhibitors generated from the two enantiomeric forms of cysteine.

Original languageEnglish (US)
Pages (from-to)1292-1301
Number of pages10
JournalChemMedChem
Volume4
Issue number8
DOIs
StatePublished - Aug 3 2009

Keywords

  • Epigenetics
  • Histone deacetylases
  • Inhibitors
  • Medicinal chemistry
  • Neuroprotection

ASJC Scopus subject areas

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

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