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Discovery and Validation of SIRT2 Inhibitors Based on Tenovin-6: Use of a 1H-NMR Method to Assess Deacetylase Activity
School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, North Haugh, St Andrews, Fife KY16 9ST, UK
Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graiciuno 8LT-02241, Vilnius, Lithuania
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden
Centre for Oncology & Molecular Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK
* Author to whom correspondence should be addressed.
Received: 14 September 2012; in revised form: 21 September 2012 / Accepted: 15 October 2012 / Published: 18 October 2012
Abstract: The search for potent and selective sirtuin inhibitors continues as chemical tools of this type are of use in helping to assign the function of this interesting class of deacetylases. Here we describe SAR studies starting from the unselective sirtuin inhibitor tenovin-6. These studies identify a sub-micromolar inhibitor that has increased selectivity for SIRT2 over SIRT1 compared to tenovin-6. In addition, a 1H-NMR-based method is developed and used to validate further this class of sirtuin inhibitors. A thermal shift analysis of SIRT2 in the presence of tenovin-6, -43, a control tenovin and the known SIRT2 inhibitor AGK2 is also presented.
Keywords: sirtuin; chemical tool; deacetylase assay; neurodegenerative diseases
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Pirrie, L.; McCarthy, A.R.; Major, L.L.; Morkūnaitė, V.; Zubrienė, A.; Matulis, D.; Lain, S.; Lebl, T.; Westwood, N.J. Discovery and Validation of SIRT2 Inhibitors Based on Tenovin-6: Use of a 1H-NMR Method to Assess Deacetylase Activity. Molecules 2012, 17, 12206-12224.
Pirrie L, McCarthy AR, Major LL, Morkūnaitė V, Zubrienė A, Matulis D, Lain S, Lebl T, Westwood NJ. Discovery and Validation of SIRT2 Inhibitors Based on Tenovin-6: Use of a 1H-NMR Method to Assess Deacetylase Activity. Molecules. 2012; 17(10):12206-12224.
Pirrie, Lisa; McCarthy, Anna R.; Major, Louise L.; Morkūnaitė, Vaida; Zubrienė, Asta; Matulis, Daumantas; Lain, Sonia; Lebl, Tomas; Westwood, Nicholas J. 2012. "Discovery and Validation of SIRT2 Inhibitors Based on Tenovin-6: Use of a 1H-NMR Method to Assess Deacetylase Activity." Molecules 17, no. 10: 12206-12224.