These authors contributed equally to this work.
Chiral Mercaptoacetamides Display Enantioselective Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection in Cortical Neuron Models of Oxidative Stress
Article first published online: 10 JAN 2012
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Special Issue: Neuroscience Drug Discovery
Volume 7, Issue 3, pages 425–439, March 5, 2012
How to Cite
Kalin, J. H., Zhang, H., Gaudrel-Grosay, S., Vistoli, G. and Kozikowski, A. P. (2012), Chiral Mercaptoacetamides Display Enantioselective Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection in Cortical Neuron Models of Oxidative Stress. ChemMedChem, 7: 425–439. doi: 10.1002/cmdc.201100522
- Issue published online: 1 MAR 2012
- Article first published online: 10 JAN 2012
- Manuscript Revised: 9 DEC 2011
- Manuscript Received: 11 NOV 2011
- Alzheimer’s Drug Discovery Foundation. Grant Number: 271210
- histone deacetylases;
- neurological agents
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.