Antiproliferative and differentiating activities of a novel series of histone deacetylase inhibitors

Monica Binaschi, Andrea Boldetti, Maurizio Gianni, Carlo Alberto Maggi, Martina Gensini, Mario Bigioni, Massimo Parlani, Alessandro Giolitti, Maddalena Fratelli, Claudia Valli, Mineko Terao, Enrico Garattini

Research output: Contribution to journalArticlepeer-review

Abstract

Histone deacetylases are promising molecular targets for the development of antitumor agents. A novel series of histone deacetylase inhibitors of the hydroxamic acid type were synthesized for structure-activity studies. Thirteen tricyclic dibenzo-diazepine, -oxazepine, and -thiazepine analogues were studied and shown to induce variable degrees of histone H3/H4 and tubulin acetylation in a cellular model of myeloid leukemia sensitive to all-trans retinoic acid (ATRA). Multiparametric correlations between acetylation of the three substrates, tumor cell growth inhibition, and ATRA-dependent cytodifferentiation were performed, providing information on the chemical functionalities governing these activities. For two analogues, antitumor activity in the animal was demonstrated.

Original languageEnglish
Pages (from-to)411-415
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume1
Issue number8
DOIs
Publication statusPublished - Nov 11 2010

Keywords

  • macrolactone
  • MDR reversing agents
  • nonnatural natural product
  • P-glycoprotein
  • Taxanes

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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