39. Sauve AA, Schramm VL (2003) Sir2 regulation by nicotinamide results from switching
between base exchange and deacetylation chemistry. Biochemistry 42(31):9249–9256.
https://doi.org/10.1021/bi034959l
40. Hu J, Jing H, Lin H (2014) Sirtuin inhibitors as anticancer agents. Future Med Chem
6(8):945–966. https://doi.org/10.4155/fmc.14.44
41. Cui H, Kamal Z, Ai T et al (2014) Discovery of potent and selective sirtuin 2 (SIRT2)
inhibitors using a fragment-based approach. J Med Chem 57(20):8340–8357. https://doi.org/
10.1021/jm500777s
42. Feldman JL, Dittenhafer-Reed KE, Kudo N et al (2015) Kinetic and structural basis for acylgroup selectivity and NAD(+) dependence in sirtuin-catalyzed deacylation. Biochemistry
54(19):3037–3050. https://doi.org/10.1021/acs.biochem.5b00150
43. Lawson M, Uciechowska U, Schemies J (2010) Inhibitors to understand molecular mechanisms of NAD(+)-dependent deacetylases (sirtuins). Biochim Biophys Acta 1799
(10–12):726–739. https://doi.org/10.1016/j.bbagrm.2010.06.003
44. Rye PT, Frick LE, Ozbal CC et al (2011) Advances in label-free screening approaches for
studying histone acetyltransferases. J Biomol Screen 16(10):1186–1195. https://doi.org/10.
1177/1087057111418653
45. Tervo AJ, Suuronen T, Kyrylenko S (2006) Discovering inhibitors of human sirtuin type 2:
novel structural scaffolds. J Med Chem 49(24):7239–7241. https://doi.org/10.1021/jm060686r
46. Yang H, Lavu S, Sinclair DA (2006) Nampt/PBEF/Visfatin: a regulator of mammalian health
and longevity? Exp Gerontol 41(8):718–726. https://doi.org/10.1016/j.exger.2006.06.003
47. Hwang ES, Song SB (2017) Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a
stimulator in cells. Cell Mol Life Sci 74(18):3347–3362. https://doi.org/10.1007/s00018-0172527-8
48. Suzuki T, Imai K, Nakagawa H et al (2006) 2-Anilinobenzamides as SIRT inhibitors.
ChemMedChem 1(10):1059–1062. https://doi.org/10.1002/cmdc.200600162
49. Suzuki T, Imai K, Imai E et al (2009a) Design, synthesis, enzyme inhibition, and tumor cell
growth inhibition of 2-anilinobenzamide derivatives as SIRT1 inhibitors. Bioorg Med Chem
17(16):5900–5905. https://doi.org/10.1016/j.bmc.2009.07.001
50. Suzuki T, Khan MN, Sawada H et al (2012) Design, synthesis, and biological activity of a
novel series of human sirtuin-2-selective inhibitors. J Med Chem 55(12):5760–5773. https://
doi.org/10.1021/jm3002108
51. Tatum PR, Sawada H, Ota Y (2014) Identification of novel SIRT2-selective inhibitors using a
click chemistry approach. Bioorg Med Chem Lett 24(8):1871–1874. https://doi.org/10.1016/j.
bmcl.2014.03.026
52. Mellini P, Itoh Y, Tsumoto H et al (2017) Potent mechanism-based sirtuin-2-selective
inhibition by an in situ generated occupant of the substrate-binding site, “selectivity pocket”
and NAD+ binding site. Chem Sci 8(9):6400–6408. https://doi.org/10.1039/c7sc02738a
53. Fatkins DG, Monnot AD, Zheng W (2006) Nε-thioacetyllysine: a multi-facet functional probe
for enzymatic protein lysine Nε-deacetylation. Bioorg Med Chem Lett 16(14):3651–3656.
https://doi.org/10.1016/j.bmcl.2006.04.075
54. Fatkins DG, Zheng W (2008) Substituting Nε-thioacetyl-lysine for Nε-acetyl-lysine in peptide
substrates as a general approach to inhibiting human NAD+-dependent protein deacetylases.
Int J Mol Sci 9(1):1–11
55. Smith BC, Denu JM (2007b) Mechanism-based inhibition of Sir2 deacetylases by thioacetyllysine peptide. Biochemistry 46(50):14478–14486. https://doi.org/10.1021/bi7013294
56. Huhtiniemi T, Suuronen T, Lahtela-Kakkonen M et al (2010) N(epsilon)-modified lysine
containing inhibitors for SIRT1 and SIRT2. Bioorg Med Chem 18(15):5616–5625. https://
doi.org/10.1016/j.bmc.2010.06.035
57. Smith BC, Denu JM (2007a) Acetyl-lysine analog peptides as mechanistic probes of protein
deacetylases. J Biol Chem 282(51):37256–37265. https://doi.org/10.1074/jbc.M707878200
84
M. Rahnasto-Rilla et al.
between base exchange and deacetylation chemistry. Biochemistry 42(31):9249–9256.
https://doi.org/10.1021/bi034959l
40. Hu J, Jing H, Lin H (2014) Sirtuin inhibitors as anticancer agents. Future Med Chem
6(8):945–966. https://doi.org/10.4155/fmc.14.44
41. Cui H, Kamal Z, Ai T et al (2014) Discovery of potent and selective sirtuin 2 (SIRT2)
inhibitors using a fragment-based approach. J Med Chem 57(20):8340–8357. https://doi.org/
10.1021/jm500777s
42. Feldman JL, Dittenhafer-Reed KE, Kudo N et al (2015) Kinetic and structural basis for acylgroup selectivity and NAD(+) dependence in sirtuin-catalyzed deacylation. Biochemistry
54(19):3037–3050. https://doi.org/10.1021/acs.biochem.5b00150
43. Lawson M, Uciechowska U, Schemies J (2010) Inhibitors to understand molecular mechanisms of NAD(+)-dependent deacetylases (sirtuins). Biochim Biophys Acta 1799
(10–12):726–739. https://doi.org/10.1016/j.bbagrm.2010.06.003
44. Rye PT, Frick LE, Ozbal CC et al (2011) Advances in label-free screening approaches for
studying histone acetyltransferases. J Biomol Screen 16(10):1186–1195. https://doi.org/10.
1177/1087057111418653
45. Tervo AJ, Suuronen T, Kyrylenko S (2006) Discovering inhibitors of human sirtuin type 2:
novel structural scaffolds. J Med Chem 49(24):7239–7241. https://doi.org/10.1021/jm060686r
46. Yang H, Lavu S, Sinclair DA (2006) Nampt/PBEF/Visfatin: a regulator of mammalian health
and longevity? Exp Gerontol 41(8):718–726. https://doi.org/10.1016/j.exger.2006.06.003
47. Hwang ES, Song SB (2017) Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a
stimulator in cells. Cell Mol Life Sci 74(18):3347–3362. https://doi.org/10.1007/s00018-0172527-8
48. Suzuki T, Imai K, Nakagawa H et al (2006) 2-Anilinobenzamides as SIRT inhibitors.
ChemMedChem 1(10):1059–1062. https://doi.org/10.1002/cmdc.200600162
49. Suzuki T, Imai K, Imai E et al (2009a) Design, synthesis, enzyme inhibition, and tumor cell
growth inhibition of 2-anilinobenzamide derivatives as SIRT1 inhibitors. Bioorg Med Chem
17(16):5900–5905. https://doi.org/10.1016/j.bmc.2009.07.001
50. Suzuki T, Khan MN, Sawada H et al (2012) Design, synthesis, and biological activity of a
novel series of human sirtuin-2-selective inhibitors. J Med Chem 55(12):5760–5773. https://
doi.org/10.1021/jm3002108
51. Tatum PR, Sawada H, Ota Y (2014) Identification of novel SIRT2-selective inhibitors using a
click chemistry approach. Bioorg Med Chem Lett 24(8):1871–1874. https://doi.org/10.1016/j.
bmcl.2014.03.026
52. Mellini P, Itoh Y, Tsumoto H et al (2017) Potent mechanism-based sirtuin-2-selective
inhibition by an in situ generated occupant of the substrate-binding site, “selectivity pocket”
and NAD+ binding site. Chem Sci 8(9):6400–6408. https://doi.org/10.1039/c7sc02738a
53. Fatkins DG, Monnot AD, Zheng W (2006) Nε-thioacetyllysine: a multi-facet functional probe
for enzymatic protein lysine Nε-deacetylation. Bioorg Med Chem Lett 16(14):3651–3656.
https://doi.org/10.1016/j.bmcl.2006.04.075
54. Fatkins DG, Zheng W (2008) Substituting Nε-thioacetyl-lysine for Nε-acetyl-lysine in peptide
substrates as a general approach to inhibiting human NAD+-dependent protein deacetylases.
Int J Mol Sci 9(1):1–11
55. Smith BC, Denu JM (2007b) Mechanism-based inhibition of Sir2 deacetylases by thioacetyllysine peptide. Biochemistry 46(50):14478–14486. https://doi.org/10.1021/bi7013294
56. Huhtiniemi T, Suuronen T, Lahtela-Kakkonen M et al (2010) N(epsilon)-modified lysine
containing inhibitors for SIRT1 and SIRT2. Bioorg Med Chem 18(15):5616–5625. https://
doi.org/10.1016/j.bmc.2010.06.035
57. Smith BC, Denu JM (2007a) Acetyl-lysine analog peptides as mechanistic probes of protein
deacetylases. J Biol Chem 282(51):37256–37265. https://doi.org/10.1074/jbc.M707878200
84
M. Rahnasto-Rilla et al.