Stereoselective HDAC inhibition from cysteine-derived zinc-binding groups.
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 IC(50) values below 1 microM. 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 microM 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.
Butler
Kyle V
KV
Department of Medicinal Chemistry, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
He
Rong
R
McLaughlin
Kathryn
K
Vistoli
Giulio
G
Langley
Brett
B
Kozikowski
Alan P
AP
D000818:Animals; D002352:Carrier Proteins; D020134:Catalytic Domain; D003198:Computer Simulation; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003553:Cystine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D020033:Protein Isoforms; C017800:zinc-binding protein; D003553:Cystine; D006655:Histone Deacetylases; D003545:Cysteine