(2-Amino-phenyl)-amides of ω-substituted alkanoic acids as new histone deacetylase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 1; pp. 283 - 287
• Main Authors: Vaisburg, Arkadii, Bernstein, Naomy, Frechette, Sylvie, Allan, Martin, Abou-Khalil, Elie, Leit, Silvana, Moradei, Oscar, Bouchain, Giliane, Wang, James, Woo, Soon Hyung, Fournel, Marielle, Yan, Pu T., Trachy-Bourget, Marie-Claude, Kalita, Ann, Beaulieu, Carole, Li, Zuomei, MacLeod, A.Robert, Besterman, Jeffrey M., Delorme, Daniel
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05.01.2004; Elsevier
• Subjects: Amides - chemistry; Amides - pharmacology; Antineoplastic agents; Biological and medical sciences; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Line, Tumor; Chemotherapy; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Humans; Medical sciences; Pharmacology. Drug treatments; Antineoplastic agent; Cell proliferation; Nitrogen heterocycle; Imide; Structure activity relation; Aromatic compound; Colon; Inhibition; Chemical synthesis; Tumor cell; Human; Enzyme; Enzyme inhibitor; Aniline derivatives; Malignant tumor; Tricyclic compound; In vivo; Chemotherapy; Experimental disease; Histone deacetylase inhibitor; Cell line; Biphenyl derivatives; Animal; Phenols; Hydrolases; Carboxamide; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.08.083

A variety of ω-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC 50 values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models. A series of benzamides ( 9 and 10) was synthesized and their biological evaluation as HDAC inhibitor is reported.