Binding mode analysis of 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide: a new synthetic histone deacetylase inhibitor inducing histone hyperacetylation growth inhibition and terminal cell differentiation

Giuseppina Nocca, Roberto Scatena, Antonello Mai, Silvio Massa, Rino Ragno, Marco Esposito, Giovanni Sbardella, Frederic Jesacher, Peter Loidl, Gunther Brosch

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66 Citations (Scopus)

Abstract

The binding mode of 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides 1a-c, belonging to a recently reported class of synthetic histone deacetylase (HDAC) inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072), into the new modeled HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. HDAC1 X-ray coordinates were obtained by virtual "mutation" of those of histone deacetylase-like protein, a bacterial HDAC homologue. In in vitro antimaize HD2 as well as antimouse HDAC1 assay, compounds 1a-c showed inhibitory activities in the low micromolar range. Similarly, 1a-c are endowed with anti-HDAC activity in vivo: on mouse A20 cells, 1a-c induced histone hyperacetylation leading to a highly increased acetylation level of H4 as compared to control histones. Results obtained with acid-urea-triton polyacrylamide gel electrophoresis have been confirmed by Western Blot experiments. Finally, compound 1a, chosen as a representative member of this class of HDAC inhibitors, resulted endowed with antiproliferative (45 and 85% cell growth inhibition at 40 and 80 microM, respectively) and cellular differentiation (18 and 21% of benzidine positive cells at the same concentrations) activities in murine erythroleukemic cells.
Original languageEnglish
Pages (from-to)1778-1784
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2002

Keywords

  • cancer
  • differentiation
  • mitosis

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