Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors

Sabrina Dallavalle, Raffaella Cincinelli, Raffaella Nannei, Lucio Merlini, Gabriella Morini, Sergio Penco, Claudio Pisano, Loredana Vesci, Marcella Barbarino, Valentina Zuco, Michelandrea De Cesare, Franco Zunino

Research output: Contribution to journalArticlepeer-review

Abstract

A series of hydroxamic acid-based histone deacetylase (HDAC) inhibitors were designed on the basis of a model of the HDAC2 binding site and synthesized. They are characterized by a cinnamic spacer, capped with a substituted phenyl group. Modifications of the spacer are also reported. In an in vitro assay with the isoenzyme HDAC2, a good correlation of the activity with the docking energy was found. In human ovarian carcinoma IGROV-1 cells, selected compounds produced significant acetylation of p53 and α-tubulin. Most compounds showed an antiproliferative activity comparable to that of SAHA. At equitoxic concentrations, the tested compounds were more effective than SAHA in inducing apoptotic cell death. Compounds selected for in vivo evaluation exhibited a significant antitumor activity on three tumor models at well tolerated doses, thus suggesting a good therapeutic index.

Original languageEnglish
Pages (from-to)1900-1912
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume44
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords

  • Antiproliferative activity
  • Histone deacetylase
  • Synthesis

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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