Polyaminohydroxamic acids and polyaminobenzamides as isoform selective histone deacetylase inhibitors

Sheeba Varghese, Thulani Senanayake, Tracey Murray-Stewart, Kim Doering, Alison Fraser, Robert A. Casero, Patrick M. Woster

Research output: Contribution to journalArticle

Abstract

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 p21waf1 and acetylated histones 3 and 4, suggesting that 17 selectively inhibits HDAC 6. PABA 22 alone minimally increased p21waf1 and acetylated histones 3 and 4 but caused dose-dependent increases in p21waf1 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.

Original languageEnglish (US)
Pages (from-to)2447-2456
Number of pages10
JournalJournal of medicinal chemistry
Volume51
Issue number8
DOIs
StatePublished - Apr 24 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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