Polyaminohydroxamic acids and polyaminobenzamides as isoform selective histone deacetylase inhibitors.
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 microM), and two PABAs inhibited HDAC >50% (5 microM). Compound 17 increased acetylated alpha-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 microM 5-azadeoxycytidine. Finally, 22 appeared to be a substrate for the polyamine transport system. None of these compounds were cytotoxic at 100 microM. PAHAs and PABAs exhibit strikingly different cellular effects from SAHA and have the potential for use in combination antitumor therapies with reduced toxicity.
Varghese
Sheeba
S
Department of Pharmaceutical Sciences, Wayne State University, 259 Mack Avenue, Detroit, Michigan 48202, USA.
Senanayake
Thulani
T
Murray-Stewart
Tracey
T
Doering
Kim
K
Fraser
Alison
A
Casero
Robert A
RA
Woster
Patrick M
PM
D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013055:Spectrophotometry, Infrared
D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes