Synthesis and Evaluation of In Vitro Activity of Novel SAHA-Like Derivatives as Histone Deacetylase Inhibitors (Abstract/Poster in atti di convegno)

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  • Synthesis and Evaluation of In Vitro Activity of Novel SAHA-Like Derivatives as Histone Deacetylase Inhibitors (Abstract/Poster in atti di convegno) (literal)
Anno
  • 2009-01-01T00:00:00+01:00 (literal)
Alternative label
  • Giuseppe Giannini, Stephen Hanessian, Luciana Auzzas, Walter Cabri, Gianfranco Battistuzzi, Loredana Vesci, Claudio Pisano (2009)
    Synthesis and Evaluation of In Vitro Activity of Novel SAHA-Like Derivatives as Histone Deacetylase Inhibitors
    in 2009 AACR (2009 American Association Cancer Research Annual Meeting), Denver (Colorado), USA
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Giuseppe Giannini, Stephen Hanessian, Luciana Auzzas, Walter Cabri, Gianfranco Battistuzzi, Loredana Vesci, Claudio Pisano (literal)
Note
  • Abstract (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Université de Montreal, Departement de Chimie, Montréal (QC), Canada Sigma Tau Industrie Farmaceutiche Riunite SpA, Pomezia (Roma), Italy (literal)
Titolo
  • Synthesis and Evaluation of In Vitro Activity of Novel SAHA-Like Derivatives as Histone Deacetylase Inhibitors (literal)
Abstract
  • Inhibition of the family of proteins generally known as Histone Deacetylases (HDACs) has emerged as a new strategy in human cancer therapy. HDACs mediate chromatin remodeling and gene expression by removal of acetyl groups from specific lysine epsilon-amino groups of histones protein backbones. HDAC inhibitors (HDACi) induce hyperacetylation of histones which causes cell-cycle arrest, differentiation and apoptosis in various tumor cell lines. Among different HDACs isoforms, are the Zn-dependent class I, II and IV varieties. Several HDACi drugs targeting these metal-dependent enzymes are in various stages of clinical trials, with only SAHA (suberoylanilide hydroxamic acid, Vorinostat) gaining FDA approval in 2006 for the treatment of advanced cutaneous T-cell lymphoma (CTCL). SAHA belongs to a wide class of HDACi that have a classical, modular construction (metal-binding moiety - linker - capping group) with structural similarities to the HDAC acetyl lysine substrate. A great number of SAHA analogues has been designed based on this simple model. Although several have reached clinical trials, none has emerged superior to SAHA in terms of potency. In our search for novel SAHA-like HDACi, we investigated the effect of introducing novel, yet unexplored zing binding motifs on the activity, as well as variation of the aliphatic chain lengh and sterochemical dependence. A series of ethers analogues were found which exhibited inhibitory activity on HDACs comparable to SAHA, and antiproliferative activity on three human cell lines higher than SAHA (Hanessian S. et al. Bioorg. Med. Chem. Lett. 2007, 17, 6261-6265). This encouraging result led to the design of a new generation of analogues, which showed inhibitory activities ranging from low to high nM, and with sub-micromolar antiproliferative activity. Results pertaining to inhibitory activities against all 11 human HDACs isoforms and on two human cell lines will be shown. (literal)
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