| Abstract
| - The reversible acetylation of histones is critical for regulation of eukaryotic gene expression.The histone deacetylase inhibitors trichostatin (TSA, 1), MS-275 (2) and suberoylanilidehydroxamic 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 usto design and synthesize polyaminohydroxamic acid (PAHA) derivatives 6−21. We felt thatPAHAs would be selectively directed to chromatin and associated histones by the positivelycharged polyamine side chain. At 1 μM, 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 wasmore potent than 2, more effective as an initiator of histone hyperacetylation, and significantlymore effective than 2 at re-expressing p21Waf1 in ML-1 leukemia cells. On the basis of theseresults, PAHAs 6−21 represent an important new chemical class of HDAC inhibitors.
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