Alkyl-Substituted Polyaminohydroxamic Acids: A Novel Class of Targeted Histone Deacetylase Inhibitors

摘要

The reversible acetylation of histones is critical for regulation of eukaryotic gene expression.The histone deacetylase inhibitors trichostatin (TSA,1),MS-275 (2) and suberoylanilide hydroxamic acid (SAHA,3) arrest growth in transformed cells and in human tumor xenografts.However,1-3 suffer from lack of specificity among the various HDAC isoforms,prompting us to design and synthesize polyaminohydroxamic acid (PAHA) derivatives 6-21.We felt that PAHAs would be selectively directed to chromatin and associated histones by the positively charged polyamine side chain.At 1muM,compounds 12,15 and 20 inhibited HDAC by 74.86,59.99 and 73.85%,respectively.Although 20 was a less potent HDAC inhibitor than 1,it was more potent than 2,more effective as an initiator of histone hyperacetylation,and significantly more effective than 2 at re-expressing p21~(Waf1) in ML-1 leukemia cells.On the basis of these results,PAHAs 6-21 represent an important new chemical class of HDAC inhibitors.