1239034-71-9Relevant articles and documents
Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells
Kalin, Jay H.,Butler, Kyle V.,Akimova, Tatiana,Hancock, Wayne W.,Kozikowski, Alan P.
, p. 639 - 651 (2012/03/11)
Second-generation Tubastatin A analogues were synthesized and evaluated for their ability to inhibit selectively histone deacetylase 6 (HDAC6). Substitutions to the carboline cap group were well-tolerated with substitution at the 2-position of both β- and γ-carbolines being optimal for HDAC6 activity and selectivity. Some compounds in this series were determined to have subnanomolar activity at HDAC6 with more than 7000 fold selectivity for HDAC6 versus HDAC1. Selected compounds were then evaluated for their ability to augment the immunosuppressive effect of Foxp3+ regulatory T cells. All compounds tested were found to enhance the ability of regulatory T cells to inhibit the mitotic division of effector T cells both in vitro and in vivo, suggesting that further investigation into the use of these compounds for the treatment of autoimmune disorders is warranted.
Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A
Butler, Kyle V.,Kalin, Jay,Brochier, Camille,Vistoli, Guilio,Langley, Brett,Kozikowski, Alan P.
supporting information; experimental part, p. 10842 - 10846 (2010/09/16)
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.
