title: Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: synthesis, biological activity, and computational evaluation.
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 α-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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Cinzia B
authors.initials: CB
authors.lastname: Botta
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Elena
authors.initials: E
authors.lastname: Cini
authors.forename: Lucia
authors.initials: L
authors.lastname: De Cesare
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Antonello
authors.initials: A
authors.lastname: Petrella
authors.forename: Francesca
authors.initials: F
authors.lastname: Rondinelli
authors.forename: Manuela
authors.initials: M
authors.lastname: Rodriquez
authors.forename: Adele
authors.initials: A
authors.lastname: Russo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010091:Oximes / Q000737:chemistry*; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism*
chemical_list: D000577:Amides; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D010091:Oximes; D006655:Histone Deacetylases; D015032:Zinc