Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors
- 19 March 2008
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 51 (8), 2447-2456
- https://doi.org/10.1021/jm701384x
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.Keywords
This publication has 30 references indexed in Scilit:
- Structural requirements of HDAC inhibitors: SAHA analogs functionalized adjacent to the hydroxamic acidBioorganic & Medicinal Chemistry Letters, 2007
- Synthesis and cancer antiproliferative activity of new histone deacetylase inhibitors: hydrophilic hydroxamates and 2-aminobenzamide-containing derivativesEuropean Journal of Medicinal Chemistry, 2006
- Histone Deacetylase Inhibitors in Cancer TherapyCancer Investigation, 2006
- Alkyl-Substituted Polyaminohydroxamic Acids: A Novel Class of Targeted Histone Deacetylase InhibitorsJournal of Medicinal Chemistry, 2005
- (1H-Imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: A novel class of potent MSK-1-inhibitorsBioorganic & Medicinal Chemistry Letters, 2005
- Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or LymphomaJournal of Clinical Oncology, 2005
- A Fluorescent Probe of Polyamine Transport Accumulates into Intracellular Acidic Vesicles via a Two-step MechanismJournal of Biological Chemistry, 2004
- Glypican-1 Is a Vehicle for Polyamine Uptake in Mammalian CellsJournal of Biological Chemistry, 2003
- Histone deacetylases and cancer: causes and therapiesNature Reviews Cancer, 2001
- Structural Specificity of Polyamines and Polyamine Analogues in the Protection of DNA from Strand Breaks Induced by Reactive Oxygen SpeciesBiochemical and Biophysical Research Communications, 1998