ORGN 668 |
| Suberolylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) protein inhibitor currently in clinical trials to treat cancer. SAHA is comprised of an anilide portion positioned at the entrance of the active site, a suberoyl chain, and a hydroxamic acid involved in binding to a catalytic metal ion. The goal of the current project is to probe the steric requirements of inhibitor activity with analogues of SAHA. Specifically, the C13 position of SAHA was examined as a site of modification due to its close proximity to the hydroxamic acid. A small synthetic library of SAHA analogues bearing a variety of substituents at the C13 position was synthesized and tested for HDAC inhibition. Interestingly, all analogues displayed 20-100 fold decreased inhibition compared to SAHA. The results suggest that the steric environment near the hydroxamic acid in the HDAC active site is significantly confined, resulting in decreased inhibitor activity. Because known HDAC inhibitors maintain similar activity to SAHA yet contain a phenyl ring in the suberoyl chain at the C13 position, the combined results indicate that only modest steric bulk near the hydroxamic acid is tolerated. Significantly, the results have implications for anti-cancer drug design, predicting that HDAC inhibitors with bulky substituents near the hydroxamic acid will have relatively low inhibitory activities.
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Asymmetric Reactions, Combinatorial Chemistry, Molecular Recognition and Self-Assembly, Proteins, Peptides, Amino Acids and Enzyme Inhibitors
8:00 PM-10:00 PM, Wednesday, March 28, 2007 Hyatt Regency Chicago -- Riverside Center, Poster
Division of Organic Chemistry |
