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Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity

Auzzas, Luciana and Larsson, Andreas and Matera, Riccardo and Baraldi, Annamaria and Deschnes-Simard, Benot and Giannini, Giuseppe and Cabri, Walter and Battistuzzi, Gianfranco and Gallo, Grazia and Ciacci, Andrea and Vesci, Loredana and Pisano, Claudio and Hanessian, Stephen (2010) Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity. Journal of Medicinal Chemistry, Vol. 53 (23), p. 8387-8399. eISSN 1520-4804. Article.

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DOI: 10.1021/jm101092u


Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors.

Item Type:Article
ID Code:5784
Uncontrolled Keywords:Histone deacetylases, cytotoxic activity, isozymes, peptidic macrocycles
Subjects:Area 03 - Scienze chimiche > CHIM/06 Chimica organica
Divisions:002 Altri enti e centri di ricerca del Nord Sardegna > CNR-Consiglio Nazionale delle Ricerche > Istituto di chimica biomolecolare, Sassari
Publisher:American Chemical Society
Deposited On:11 May 2011 09:05

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