N-(2-Amino-phenyl)-4-(heteroarylmethyl)-benzamides as new histone deacetylase inhibitors

A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides of general structure 10 were designed, synthesized, and evaluated as histone deacetylase (HDAC) inhibitors. A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inh...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-12, Vol.17 (24), p.6729-6733
Main Authors: Vaisburg, Arkadii, Paquin, Isabelle, Bernstein, Naomy, Frechette, Sylvie, Gaudette, Frederic, Leit, Silvana, Moradei, Oscar, Raeppel, Stephane, Zhou, Nancy, Bouchain, Giliane, Woo, Soon Hyung, Jin, Zhiyun, Gillespie, Jeff, Wang, James, Fournel, Marielle, Yan, Pu Theresa, Trachy-Bourget, Marie-Claude, Robert, Marie-France, Lu, Aihua, Yuk, Jimmy, Rahil, Jubrail, MacLeod, A. Robert, Besterman, Jeffrey M., Li, Zuomei, Delorme, Daniel
Format: Article
Language:English
Subjects:
Amination
Animals
Antineoplastic agents
Benzamides
Benzamides - chemistry
Benzamides - pharmacology
Binding Sites
Biological and medical sciences
Cancer cell proliferation
Cell Line
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General aspects
HDAC
Histone Deacetylase Inhibitors
Histone Deacetylases - chemistry
Histone Deacetylases - metabolism
Humans
Medical sciences
Methylation
Mice
Models, Molecular
Molecular Structure
Niacin - pharmacology
ortho-Aminobenzoates - chemistry
Pharmacology. Drug treatments
Structure-Activity Relationship
Urea - chemistry
Vasodilation - drug effects
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Summary:A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides of general structure 10 were designed, synthesized, and evaluated as histone deacetylase (HDAC) inhibitors. A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC 50 values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21 WAF1/Cip1, and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.10.050