Oxime Amides as a Novel Zinc Binding Group in Histone Deacetylase Inhibitors: Synthesis, Biological Activity, and Computational Evaluation

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• 作者：Cinzia B. Botta ; Walter Cabri ; Elena Cini ; Lucia De Cesare ; Caterina Fattorusso ; Giuseppe Giannini ; Marco Persico ; Antonello Petrella ; Francesca Rondinelli ; Manuela Rodriquez ; Adele Russo ; Maurizio Taddei
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2165-2182
• 全文大小：1248K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

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 鈥渉it鈥?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 伪-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.