Solid phase synthesis of hydroxamate peptides for histone deacetylase inhibition

Abstract

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.