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131. Spires-Jones TL, Fox LM, Rozkalne A et al (2012) Inhibition of Sirtuin 2 with sulfobenzoic
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132. Chopra V, Quinti L, Kim J et al (2012) The sirtuin 2 inhibitor AK-7 is neuroprotective in
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133. Taylor DM, Balabadra U, Xiang Z et al (2011) A brain-permeable small molecule reduces
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134. Khanfar MA, Quinti L, Wang H et al (2014) Development and characterization of 3(Benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors. Eur J Med Chem
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135. Guan Q, Wang M, Chen H et al (2016) Aging-related 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-induced neurochemical and behavioral deficits and redox dysfunction:
improvement by AK-7. Exp Gerontol 82:19–29. https://doi.org/10.1016/j.exger.2016.05.011
136. Szegő ÉM, Gerhardt E, Outeiro TF (2017) Sirtuin 2 enhances dopaminergic differentiation via
the AKT/GSK-3β/β-catenin pathway. Neurobiol Aging 56:7–16. https://doi.org/10.1016/j.
neurobiolaging.2017.04.001
137. Quinti L, Casale M, Moniot S et al (2016) SIRT2- and NRF2-targeting thiazole-containing
compound with therapeutic activity in Huntington’s disease models. Cell Chem Biol 23
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138. Howitz KT, Bitterman KJ, Cohen HY et al (2003) Small molecule activators of sirtuins extend
Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196. https://doi.org/10.1038/
nature01960
139. Trapp J, Meier R, Hongwiset D et al (2007) Structure-activity studies on suramin analogues as
inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem 2(10):1419–
1431. https://doi.org/10.1002/cmdc.200700003
140. Tervo AJ, Kyrylenko S, Niskanen P et al (2004) An in silico approach to discovering novel
inhibitors of human sirtuin type 2. J Med Chem 47(25):6292–6298. https://doi.org/10.1021/
jm049933m
141. Kiviranta PH, Leppänen J, Kyrylenko S et al (2006) N,N
0 -Bisbenzylidenebenzene-1,4diamines and N,N
0 -bisbenzylidenenaphthalene-1,4-diamines as sirtuin type 2 (SIRT2) inhibitors. J Med Chem 49(26):7907–7911. https://doi.org/10.1021/jm060566j
142. Kiviranta PH, Leppänen J, Rinne VM et al (2007) N-(3-(4-Hydroxyphenyl)-propenoyl)-amino
acid tryptamides as SIRT2 inhibitors. Bioorg Med Chem Lett 17(9):2448–2451. https://doi.
org/10.1016/j.bmcl.2007.02.023
143. Huhtiniemi T, Suuronen T, Rinne VM et al (2008) Oxadiazole-carbonylaminothioureas as
SIRT1 and SIRT2 inhibitors. J Med Chem 51(15):4377–4380. https://doi.org/10.1021/
jm800639h
144. Moniot S, Forgione M, Lucidi A et al (2017) Development of 1,2,4-oxadiazoles as potent and
selective inhibitors of the human deacetylase sirtuin 2: structure-activity relationship, X-ray
crystal structure, and anticancer activity. J Med Chem 60(6):2344–2360. https://doi.org/10.
1021/acs.jmedchem.6b01609
145. Lain S, Hollick JJ, Campbell J et al (2008) Discovery, in vivo activity, and mechanism of
action of a small-molecule p53 activator. Cancer Cell 13(5):454–463. https://doi.org/10.1016/
j.ccr.2008.03.004
146. Sunami Y, Araki M, Hironaka Y et al (2013) Inhibition of the NAD-dependent protein
deacetylase SIRT2 induces granulocytic differentiation in human leukemia cells. PLoS One
8(2):e57633. https://doi.org/10.1371/journal.pone.0057633
Sirtuin Inhibitors and Activators
89
decreasing sterol biosynthesis. Proc Natl Acad Sci U S A 107(17):7927–7932. https://doi.org/
10.1073/pnas.1002924107
131. Spires-Jones TL, Fox LM, Rozkalne A et al (2012) Inhibition of Sirtuin 2 with sulfobenzoic
acid derivative AK1 is non-toxic and potentially neuroprotective in a mouse model of
frontotemporal dementia. Front Pharmacol 3:42. https://doi.org/10.3389/fphar.2012.00042
132. Chopra V, Quinti L, Kim J et al (2012) The sirtuin 2 inhibitor AK-7 is neuroprotective in
Huntington’s disease mouse models. Cell Rep 2(6):1492–1497. https://doi.org/10.1016/j.
celrep.2012.11.001
133. Taylor DM, Balabadra U, Xiang Z et al (2011) A brain-permeable small molecule reduces
neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase. ACS Chem Biol 6(6):540–
546. https://doi.org/10.1021/cb100376q
134. Khanfar MA, Quinti L, Wang H et al (2014) Development and characterization of 3(Benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors. Eur J Med Chem
76:414–426. https://doi.org/10.1016/j.ejmech.2014.02.003
135. Guan Q, Wang M, Chen H et al (2016) Aging-related 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-induced neurochemical and behavioral deficits and redox dysfunction:
improvement by AK-7. Exp Gerontol 82:19–29. https://doi.org/10.1016/j.exger.2016.05.011
136. Szegő ÉM, Gerhardt E, Outeiro TF (2017) Sirtuin 2 enhances dopaminergic differentiation via
the AKT/GSK-3β/β-catenin pathway. Neurobiol Aging 56:7–16. https://doi.org/10.1016/j.
neurobiolaging.2017.04.001
137. Quinti L, Casale M, Moniot S et al (2016) SIRT2- and NRF2-targeting thiazole-containing
compound with therapeutic activity in Huntington’s disease models. Cell Chem Biol 23
(7):849–861. https://doi.org/10.1016/j.chembiol.2016.05.015
138. Howitz KT, Bitterman KJ, Cohen HY et al (2003) Small molecule activators of sirtuins extend
Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196. https://doi.org/10.1038/
nature01960
139. Trapp J, Meier R, Hongwiset D et al (2007) Structure-activity studies on suramin analogues as
inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem 2(10):1419–
1431. https://doi.org/10.1002/cmdc.200700003
140. Tervo AJ, Kyrylenko S, Niskanen P et al (2004) An in silico approach to discovering novel
inhibitors of human sirtuin type 2. J Med Chem 47(25):6292–6298. https://doi.org/10.1021/
jm049933m
141. Kiviranta PH, Leppänen J, Kyrylenko S et al (2006) N,N
0 -Bisbenzylidenebenzene-1,4diamines and N,N
0 -bisbenzylidenenaphthalene-1,4-diamines as sirtuin type 2 (SIRT2) inhibitors. J Med Chem 49(26):7907–7911. https://doi.org/10.1021/jm060566j
142. Kiviranta PH, Leppänen J, Rinne VM et al (2007) N-(3-(4-Hydroxyphenyl)-propenoyl)-amino
acid tryptamides as SIRT2 inhibitors. Bioorg Med Chem Lett 17(9):2448–2451. https://doi.
org/10.1016/j.bmcl.2007.02.023
143. Huhtiniemi T, Suuronen T, Rinne VM et al (2008) Oxadiazole-carbonylaminothioureas as
SIRT1 and SIRT2 inhibitors. J Med Chem 51(15):4377–4380. https://doi.org/10.1021/
jm800639h
144. Moniot S, Forgione M, Lucidi A et al (2017) Development of 1,2,4-oxadiazoles as potent and
selective inhibitors of the human deacetylase sirtuin 2: structure-activity relationship, X-ray
crystal structure, and anticancer activity. J Med Chem 60(6):2344–2360. https://doi.org/10.
1021/acs.jmedchem.6b01609
145. Lain S, Hollick JJ, Campbell J et al (2008) Discovery, in vivo activity, and mechanism of
action of a small-molecule p53 activator. Cancer Cell 13(5):454–463. https://doi.org/10.1016/
j.ccr.2008.03.004
146. Sunami Y, Araki M, Hironaka Y et al (2013) Inhibition of the NAD-dependent protein
deacetylase SIRT2 induces granulocytic differentiation in human leukemia cells. PLoS One
8(2):e57633. https://doi.org/10.1371/journal.pone.0057633
Sirtuin Inhibitors and Activators
89