Polyaminohydroxamic acids and polyaminobenzamides as isoform selective histone deacetylase inhibitors

摘要

A series of polyaminohydroxamic acids (PAHAs) and polyaminobenzamides (PABAs) were synthesized and evaluated as isoform-selective histone deacetylase (HDAC) inhibitors. These analogues contain a polyamine chain to increase affinity for chromatin and facilitate cellular import. Seven PAHAs inhibited HDAC >50% (1 mu M), and two PABAs inhibited HDAC >50% (5 mu M). Compound 17 increased acetylated a-tubulin in HCT1 16 colon tumor cells 253-fold but only modestly increased p21(waf1) and acetylated histories 3 and 4, suggesting that 17 selectively inhibits HDAC 6. PABA 22 alone minimally increased p21(waf1) and acetylated histories 3 and 4 but caused dose-dependent increases in p21(waf1) in combination with 0.1 mu M 5-azadeoxycytidine. Finally, 22 appeared to be a substrate for the polyamine transport system. None of these compounds were cytotoxic at 100 mu M. PAHAs and PABAs exhibit strikingly different cellular effects from SAHA and have the potential for use in combination antitumor therapies with reduced toxicity.