Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

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• 作者：Sheeba Varghese ; Thulani Senanayake ; Tracey Murray-Stewart ; Kim Doering ; Alison Fraser ; Robert A. Casero Jr. ; Patrick M. Woster
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 24, 2008
• 年：2008
• 卷：51
• 期：8
• 页码：2447 - 2456
• 全文大小：620K
• 年卷期：v.51,no.8(April 24, 2008)
• ISSN：1520-4804

文摘

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 µM), and two PABAs inhibited HDAC >50% (5 µM). Compound 17 increased acetylated α-tubulin in HCT116 colon tumor cells 253-fold but only modestly increased p21^waf1 and acetylated histones 3 and 4, suggesting that 17 selectively inhibits HDAC 6. PABA 22 alone minimally increased p21^waf1 and acetylated histones 3 and 4 but caused dose-dependent increases in p21^waf1 in combination with 0.1 µM 5-azadeoxycytidine. Finally, 22 appeared to be a substrate for the polyamine transport system. None of these compounds were cytotoxic at 100 µM. PAHAs and PABAs exhibit strikingly different cellular effects from SAHA and have the potential for use in combination antitumor therapies with reduced toxicity.