Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A

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• 作者：Kyle V. Butler ; Jay Kalin ; Camille Brochier ; Guilio Vistoli ; Brett Langley ; Alan P. Kozikowski
• 刊名：Journal of the American Chemical Society
• 出版年：2010
• 出版时间：August 11, 2010
• 年：2010
• 卷：132
• 期：31
• 页码：10842-10846
• 全文大小：236K
• 年卷期：v.132,no.31(August 11, 2010)
• ISSN：1520-5126

文摘

Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated α-tubulin, but not histone, consistent with its HDAC6 selectivity. Tubastatin A also conferred dose-dependent protection in primary cortical neuron cultures against glutathione depletion-induced oxidative stress. Importantly, when given alone at all concentrations tested, this hydroxamate-containing HDAC6-selective compound displayed no neuronal toxicity, thus, forecasting the potential application of this agent and its analogues to neurodegenerative conditions.