Structurally Simple Trichostatin A-Like Straight Chain Hydroxamates as Potent Histone Deacetylase Inhibitors

A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity w...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-06, Vol.45 (13), p.2877-2885
Main Authors: Woo, Soon Hyung, Frechette, Sylvie, Khalil, Elie Abou, Bouchain, Giliane, Vaisburg, Arkadii, Bernstein, Naomy, Moradei, Oscar, Leit, Silvana, Allan, Martin, Fournel, Marielle, Trachy-Bourget, Marie-Claude, Li, Zuomei, Besterman, Jeffrey M, Delorme, Daniel
Format: Article
Language:English
Subjects:
Acetylation
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Blotting, Western
Cell Division - drug effects
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - biosynthesis
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General aspects
Histone Deacetylase Inhibitors
Histones - drug effects
Humans
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Medical sciences
Pharmacology. Drug treatments
Recombinant Proteins - antagonists & inhibitors
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC50 values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure−activity relationship results from enzyme inhibition and alterations in cellular function.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020154k