Design and synthesis of 4-[( s-triazin-2-ylamino)methyl]- N-(2-aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 3; pp. 1067 - 1071
• Main Authors: Paquin, Isabelle, Raeppel, Stéphane, Leit, Silvana, Gaudette, Frédéric, Zhou, Nancy, Moradei, Oscar, Saavedra, Oscar, Bernstein, Naomy, Raeppel, Franck, Bouchain, Giliane, Fréchette, Sylvie, Woo, Soon H., Vaisburg, Arkadii, Fournel, Marielle, Kalita, Ann, Robert, Marie-France, Lu, Aihua, Trachy-Bourget, Marie-Claude, Yan, Pu Theresa, Liu, Jianhong, Rahil, Jubrail, MacLeod, A. Robert, Besterman, Jeffrey M., Li, Zuomei, Delorme, Daniel
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2008; Elsevier
• Subjects: Animals; Anti-proliferative activity; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzamides; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Biological and medical sciences; Disease Models, Animal; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; HDAC inhibitor; Histone Deacetylase Inhibitors; Histone deacetylases (HDACs); Humans; Inhibitory Concentration 50; Medical sciences; Mice; Pharmacology. Drug treatments; Pyrimidines - pharmacology; s-Triazine; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; HDAC inhibitor; Benzamides; Anti-proliferative activity; s-Triazine; Histone deacetylases (HDACs); Antineoplastic agent; Solid tumor; Purine derivatives; Anti- proliferative activity; Colon; Chemical synthesis; Tumor cell; Human; Enzyme; Rodentia; Enzyme inhibitor; Aniline derivatives; In vitro; Biological activity; In vivo; Vertebrata; Histone deacetylase inhibitor; Mammalia; Cell line; Mouse; Animal; Triazine derivatives; Benzamide derivatives; Pyrimidine derivatives; Hydrolases; Cyclopentane derivatives; Aromatic amine
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.12.009

The synthesis and biological evaluation as histone deacetylase (HDACs) inhibitors of a variety of 4-(heteroarylaminomethyl)- N-(2-aminophenyl)-benzamides of the general structure shown is presented herein. Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)- N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC 50 values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.