Synthesis and Biological Evaluation of N-Hydroxyphenylacrylamides and N-Hydroxypyridin-2-ylacrylamides as Novel Histone Deacetylase Inhibitors

• Published in: Journal of medicinal chemistry 2010-01, Vol.53 (2), p.822-839
• Main Authors: Thaler, Florian, Colombo, Andrea, Mai, Antonello, Amici, Raffaella, Bigogno, Chiara, Boggio, Roberto, Cappa, Anna, Carrara, Simone, Cataudella, Tiziana, Fusar, Fulvia, Gianti, Eleonora, di Ventimiglia, Samuele Joppolo, Moroni, Maurizio, Munari, Davide, Pain, Gilles, Regalia, Nickolas, Sartori, Luca, Vultaggio, Stefania, Dondio, Giulio, Gagliardi, Stefania, Minucci, Saverio, Mercurio, Ciro, Varasi, Mario
• Format: Article
• Language: English
• Subjects: Acrylamides - chemical synthesis; Acrylamides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Benzene Derivatives; Cell Proliferation - drug effects; Colonic Neoplasms - drug therapy; Drug Stability; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; HeLa Cells; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - pharmacokinetics; Histone Deacetylase Inhibitors - therapeutic use; Humans; Pyridines; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901502p

The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.