Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors

Florian Thaler, Andrea Colombo, Antonello Mai, Raffaella Amici, Chiara Bigogno, Roberto Boggio, Anna Cappa, Simone Carrara, Tiziana Cataudella, Fulvia Fusar, Eleonora Gianti, Samuele Joppolo Di Ventimiglia, Maurizio Moroni, Davide Munari, Gilles Pain, Nickolas Regalia, Luca Sartori, Stefania Vultaggio, Giulio Dondio, Stefania GagliardiSaverio Minucci, Ciro Mercurio, Mario Varasi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)822-839
Number of pages18
JournalJournal of Medicinal Chemistry
Volume53
Issue number2
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Thaler, F., Colombo, A., Mai, A., Amici, R., Bigogno, C., Boggio, R., Cappa, A., Carrara, S., Cataudella, T., Fusar, F., Gianti, E., Di Ventimiglia, S. J., Moroni, M., Munari, D., Pain, G., Regalia, N., Sartori, L., Vultaggio, S., Dondio, G., ... Varasi, M. (2010). Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors. Journal of Medicinal Chemistry, 53(2), 822-839. https://doi.org/10.1021/jm901502p