Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: synthesis, biological activity, and computational evaluation.

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Botta CB, Cabri W, Cini E, De Cesare L, Fattorusso C, Giannini G, Persico M, Petrella A, Rondinelli F, Rodriquez M, Russo A, Taddei M

Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: synthesis, biological activity, and computational evaluation.

J Med Chem. 2011 Apr 14;54(7):2165-82. doi: 10.1021/jm101373a. Epub 2011 Mar 18.

PubMed ID
21417297 [ View in PubMed
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Abstract

Several oxime containing molecules, characterized by a SAHA-like structure, were explored to select a potentially new biasing binding element for the zinc in HDAC catalytic site. All compounds were evaluated for their in vitro inhibitory activity against the 11 human HDACs isoforms. After identification of a "hit" molecule, a programmed variation at the cap group and at the linker was carried out in order to increase HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed increased activity against a number of HDAC isoforms, even if their overall activity range is still far from the inhibition values reported for SAHA. Moreover, different from what was reported for their hydroxamic acid analogues the new alpha-oxime amide derivatives do not select between class I and class II HDACs; rather they target specific isoforms in each class. These somehow contradictory results were finally rationalized by a computational assisted SAR, which gave us the chance to understand how the oxime derivatives interact with the catalytic site and justify the observed activity profile.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)61N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)240N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)250N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)100N/AN/ADetails