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An orthogonal protecting group strategy was devised to synthesize hydroxamic acid containing peptides for biomimetic histone deacetylase (HDAC) inhibition. The basic building block was a protected aminosuberic acid (Asu) derivative bearing a protected hydroxamate in the side-chain, related closely to HDAC inhibitors that are transition-state analogs of acetyllysine. These inhibitors include suberoylanilide hydroxamic acid (SAHA), currently being used to treat a variety of human cancers. This strategy was employed to synthesize a series of nonameric peptides related to actual HDAC substrates, derived from known sites of acetylation/deacetylation on the N-terminal tails of the histone core proteins H2A, H2B, H3, and H4. In each case the lysine residue was replaced by a hydroxamate-bearing side chain, to mimic the endogenous site of deacetylation. Mass spectrometry and high performance liquid chromatography (HPLC) confirmed the success of automated solid-phase synthesis. These results suggest facile synthesis of a new class of HDAC inhibitors that may have enhanced selectivity for specific HDAC isoforms. |
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