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98. Mahajan SS, Scian M, Sripathy S et al (2014) Development of pyrazolone and isoxazol-5-one
cambinol analogues as sirtuin inhibitors. J Med Chem 57(8):3283–3294. https://doi.org/10.
1021/jm4018064
99. Medda F, Joseph TL, Pirrie L et al (2011) N1-Benzyl substituted cambinol analogues as
isozyme selective inhibitors of the sirtuin family of proteins deacetylases. Med Chem
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100. Rotili D, Carafa V, Tarantino D et al (2011) Simplification of the tetracyclic SIRT1-selective
inhibitor MC2141: coumarin- and pyrimidine-based SIRT1/2 inhibitors with different
selectivity profile. Bioorg Med Chem 19(12):3659–3668. https://doi.org/10.1016/j.bmc.
2011.01.025
101. Rotili D, Tarantino D, Carafa V et al (2012a) Benzodeazaoxaflavins as sirtuin inhibitors with
antiproliferative properties in cancer stem cells. J Med Chem 55(18):8193–8197. https://doi.
org/10.1021/jm301115r
102. Napper AD, Hixon J, McDonagh T et al (2005) Discovery of indoles as potent and selective
inhibitors of the deacetylase SIRT1. J Med Chem 48(25):8045–8054. https://doi.org/10.1021/
jm050522v
103. Solomon JM, Pasupuleti R, Xu L et al (2006) Inhibition of SIRT1 catalytic activity increases
p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol
26(1):28–38. https://doi.org/10.1128/MCB.26.1.28-38.2006
104. Zhao X, Allison D, Condon B et al (2013) The 2.5 Å crystal structure of the SIRT1 catalytic
domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue)
reveals a novel mechanism of histone deacetylase inhibition. J Med Chem 56(3):963–969.
https://doi.org/10.1021/jm301431y
105. Gertz M, Fischer F, Nguyen GTT (2013) Ex-527 inhibits Sirtuins by exploiting their unique
NAD+-dependent deacetylation mechanism. Proc Natl Acad Sci U S A 110(30):E2772–
E2781. https://doi.org/10.1073/pnas.1303628110
106. Sasca D, Hähnel PS, Szybinski J et al (2014) SIRT1 prevents genotoxic stress-induced p53
activation in acute myeloid leukemia. Blood 124(1):121–133. https://doi.org/10.1182/blood2013-11-538819
107. Kim BS, Lee CH, Chang GE et al (2016) A potent and selective small molecule inhibitor of
sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons. Sci Rep
6:34324. https://doi.org/10.1038/srep34324
108. Süssmuth SD, Haider S, Landwehrmeyer GB et al (2015) An exploratory double-blind,
randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington’s
disease. Br J Clin Pharmacol 79(3):465–476. https://doi.org/10.1111/bcp.12512
109. Westerberg G, Chiesa JA, Andersen CA et al (2015) Safety, pharmacokinetics, pharmacogenomics and QT concentration-effect modelling of the SirT1 inhibitor selisistat in healthy
volunteers. Br J Clin Pharmacol 79(3):477–491. https://doi.org/10.1111/bcp.12513
110. Mellini P, Carafa V, Di Rienzo B et al (2012) Carprofen analogues as sirtuin inhibitors:
enzyme and cellular studies. ChemMedChem 7(11):1905–1908. https://doi.org/10.1002/
cmdc.201200318
111. Zhang Y, Au Q, Zhang M et al (2009) Identification of a small molecule SIRT2 inhibitor with
selective tumor cytotoxicity. Biochem Biophys Res Commun 386(4):729–733. https://doi.org/
10.1016/j.bbrc.2009.06.113
112. Huber K, Schemies J, Uciechowska U et al (2010) Novel 3-arylideneindolin-2-ones as inhibitors
of NAD+-dependent histone deacetylases (sirtuins). J Med Chem 53(3):1383–1386. https://doi.
org/10.1021/jm901055u
113. Suenkel B, Fischer F, Steegborn C (2013) Inhibition of the human deacylase Sirtuin 5 by the
indole GW5074. Bioorg Med Chem Lett 23(1):143–146. https://doi.org/10.1016/j.bmcl.2012.
10.136
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synthesis, biological evaluation, and rationalization of activity. J Med Chem 52
(9):2673–2682. https://doi.org/10.1021/jm8014298
98. Mahajan SS, Scian M, Sripathy S et al (2014) Development of pyrazolone and isoxazol-5-one
cambinol analogues as sirtuin inhibitors. J Med Chem 57(8):3283–3294. https://doi.org/10.
1021/jm4018064
99. Medda F, Joseph TL, Pirrie L et al (2011) N1-Benzyl substituted cambinol analogues as
isozyme selective inhibitors of the sirtuin family of proteins deacetylases. Med Chem
Commun 2(7):611–615. https://doi.org/10.1039/C1MD00023C
100. Rotili D, Carafa V, Tarantino D et al (2011) Simplification of the tetracyclic SIRT1-selective
inhibitor MC2141: coumarin- and pyrimidine-based SIRT1/2 inhibitors with different
selectivity profile. Bioorg Med Chem 19(12):3659–3668. https://doi.org/10.1016/j.bmc.
2011.01.025
101. Rotili D, Tarantino D, Carafa V et al (2012a) Benzodeazaoxaflavins as sirtuin inhibitors with
antiproliferative properties in cancer stem cells. J Med Chem 55(18):8193–8197. https://doi.
org/10.1021/jm301115r
102. Napper AD, Hixon J, McDonagh T et al (2005) Discovery of indoles as potent and selective
inhibitors of the deacetylase SIRT1. J Med Chem 48(25):8045–8054. https://doi.org/10.1021/
jm050522v
103. Solomon JM, Pasupuleti R, Xu L et al (2006) Inhibition of SIRT1 catalytic activity increases
p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol
26(1):28–38. https://doi.org/10.1128/MCB.26.1.28-38.2006
104. Zhao X, Allison D, Condon B et al (2013) The 2.5 Å crystal structure of the SIRT1 catalytic
domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue)
reveals a novel mechanism of histone deacetylase inhibition. J Med Chem 56(3):963–969.
https://doi.org/10.1021/jm301431y
105. Gertz M, Fischer F, Nguyen GTT (2013) Ex-527 inhibits Sirtuins by exploiting their unique
NAD+-dependent deacetylation mechanism. Proc Natl Acad Sci U S A 110(30):E2772–
E2781. https://doi.org/10.1073/pnas.1303628110
106. Sasca D, Hähnel PS, Szybinski J et al (2014) SIRT1 prevents genotoxic stress-induced p53
activation in acute myeloid leukemia. Blood 124(1):121–133. https://doi.org/10.1182/blood2013-11-538819
107. Kim BS, Lee CH, Chang GE et al (2016) A potent and selective small molecule inhibitor of
sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons. Sci Rep
6:34324. https://doi.org/10.1038/srep34324
108. Süssmuth SD, Haider S, Landwehrmeyer GB et al (2015) An exploratory double-blind,
randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington’s
disease. Br J Clin Pharmacol 79(3):465–476. https://doi.org/10.1111/bcp.12512
109. Westerberg G, Chiesa JA, Andersen CA et al (2015) Safety, pharmacokinetics, pharmacogenomics and QT concentration-effect modelling of the SirT1 inhibitor selisistat in healthy
volunteers. Br J Clin Pharmacol 79(3):477–491. https://doi.org/10.1111/bcp.12513
110. Mellini P, Carafa V, Di Rienzo B et al (2012) Carprofen analogues as sirtuin inhibitors:
enzyme and cellular studies. ChemMedChem 7(11):1905–1908. https://doi.org/10.1002/
cmdc.201200318
111. Zhang Y, Au Q, Zhang M et al (2009) Identification of a small molecule SIRT2 inhibitor with
selective tumor cytotoxicity. Biochem Biophys Res Commun 386(4):729–733. https://doi.org/
10.1016/j.bbrc.2009.06.113
112. Huber K, Schemies J, Uciechowska U et al (2010) Novel 3-arylideneindolin-2-ones as inhibitors
of NAD+-dependent histone deacetylases (sirtuins). J Med Chem 53(3):1383–1386. https://doi.
org/10.1021/jm901055u
113. Suenkel B, Fischer F, Steegborn C (2013) Inhibition of the human deacylase Sirtuin 5 by the
indole GW5074. Bioorg Med Chem Lett 23(1):143–146. https://doi.org/10.1016/j.bmcl.2012.
10.136
Sirtuin Inhibitors and Activators
87