58. Kiviranta PH, Suuronen T, Wallén EAA et al (2009) N(ε)-thioacetyllysine-containing tri-,
tetra-, and pentapeptides as SIRT1 and SIRT2 inhibitors. J Med Chem 52(7):2153–2156.
https://doi.org/10.1021/jm801401k
59. Kokkonen P, Rahnasto-Rilla M, Kiviranta PH et al (2012) Peptides and pseudopeptides as
SIRT6 deacetylation inhibitors. ACS Med Chem Lett 3(12):969–974. https://doi.org/10.1021/
ml300139n
60. Huang Y, Liu J, Yan L et al (2016) Simple N(ε)-thioacetyl-lysine-containing cyclic peptides
exhibiting highly potent sirtuin inhibition. Bioorg Med Chem Lett 26(6):1612–1617. https://
doi.org/10.1016/j.bmcl.2016.01.086
61. Morimoto J, Hayashi Y, Suga H (2012) Discovery of macrocyclic peptides armed with a
mechanism-based warhead: isoform-selective inhibition of human deacetylase SIRT2. Angew
Chem Int Ed Engl 51(14):3423–3427. https://doi.org/10.1002/anie.201108118
62. Yamagata K, Goto Y, Nishimasu H et al (2014) Structural basis for potent inhibition of
SIRT2 deacetylase by a macrocyclic peptide inducing dynamic structural change. Structure 22
(2):345–352. https://doi.org/10.1016/j.str.2013.12.001
63. Asaba T, Suzuki T, Ueda R et al (2009) Inhibition of human sirtuins by in situ generation of an
acetylated lysine-ADP-ribose conjugate. J Am Chem Soc 131(20):6989–6996. https://doi.org/
10.1021/ja807083y
64. Suzuki T, Asaba T, Imai E et al (2009b) Identification of a cell-active non-peptide sirtuin
inhibitor containing N-thioacetyl lysine. Bioorg Med Chem Lett 19(19):5670–5672. https://
doi.org/10.1016/j.bmcl.2009.08.028
65. Jing H, Hu J, He B et al (2016) A SIRT2-selective inhibitor promotes c-Myc oncoprotein
degradation and exhibits broad anticancer activity. Cancer Cell 29(3):297–310. https://doi.org/
10.1016/j.ccell.2016.02.007
66. Huhtiniemi T, Salo HS, Suuronen T et al (2011) Structure-based design of pseudopeptidic
inhibitors for SIRT1 and SIRT2. J Med Chem 54(19):6456–6468. https://doi.org/10.1021/
jm200590k
67. Mellini P, Kokkola T, Suuronen T et al (2013) Screen of pseudopeptidic inhibitors of human
sirtuins 1-3: two lead compounds with antiproliferative effects in cancer cells. J Med Chem
56(17):6681–6695. https://doi.org/10.1021/jm400438k
68. He B, Du J, Lin H (2012) Thiosuccinyl peptides as Sirt5-specific inhibitors. J Am Chem Soc
134(4):1992–1995. https://doi.org/10.1021/ja2090417
69. Roessler C, Nowak T, Pannek M et al (2014) Chemical probing of the human sirtuin 5 active
site reveals its substrate acyl specificity and peptide-based inhibitors. Angew Chem Int Ed
Engl 53(40):10728–10732. https://doi.org/10.1002/anie.201402679
70. Zang W, Hao Y, Wang Z et al (2015) Novel thiourea-based sirtuin inhibitory warheads. Bioorg
Med Chem Lett 25(16):3319–3324. https://doi.org/10.1016/j.bmcl.2015.05.058
71. Liu J, Huang Y, Zheng W (2016) A selective cyclic peptidic human SIRT5 inhibitor.
Molecules 21(9):1217. https://doi.org/10.3390/molecules21091217
72. Wang J, Zang W, Liu J et al (2017) Bivalent SIRT1 inhibitors. Bioorg Med Chem Lett
27(2):180–186. https://doi.org/10.1016/j.bmcl.2016.11.082
73. Li L, Wang L, Li L et al (2012) Activation of p53 by SIRT1 inhibition enhances elimination of
CML leukemia stem cells in combination with imatinib. Cancer Cell 21(2):266–281. https://
doi.org/10.1016/j.ccr.2011.12.020
74. Ng FW, Wijaya L, Tang BL (2015) SIRT1 in the brain-connections with aging-associated
disorders and lifespan. Front Cell Neurosci 9:64. https://doi.org/10.3389/fncel.2015.00064
75. Parenti MD, Grozio A, Bauer I et al (2014) Discovery of novel and selective SIRT6 inhibitors.
J Med Chem 57(11):4796–4804. https://doi.org/10.1021/jm500487d
76. Rahnasto-Rilla M, Tyni J, Huovinen M et al (2018) Natural polyphenols as sirtuin 6 modulators. Sci Rep 8(1):4163. https://doi.org/10.1038/s41598-018-22388-5
77. Kim JH, Kim D, Cho SJ et al (2018) Identification of a novel SIRT7 inhibitor as anticancer
drug candidate. Biochem Biophys Res Commun 508(2):451–457. https://doi.org/10.1016/j.
bbrc.2018.11.120
Sirtuin Inhibitors and Activators
85
tetra-, and pentapeptides as SIRT1 and SIRT2 inhibitors. J Med Chem 52(7):2153–2156.
https://doi.org/10.1021/jm801401k
59. Kokkonen P, Rahnasto-Rilla M, Kiviranta PH et al (2012) Peptides and pseudopeptides as
SIRT6 deacetylation inhibitors. ACS Med Chem Lett 3(12):969–974. https://doi.org/10.1021/
ml300139n
60. Huang Y, Liu J, Yan L et al (2016) Simple N(ε)-thioacetyl-lysine-containing cyclic peptides
exhibiting highly potent sirtuin inhibition. Bioorg Med Chem Lett 26(6):1612–1617. https://
doi.org/10.1016/j.bmcl.2016.01.086
61. Morimoto J, Hayashi Y, Suga H (2012) Discovery of macrocyclic peptides armed with a
mechanism-based warhead: isoform-selective inhibition of human deacetylase SIRT2. Angew
Chem Int Ed Engl 51(14):3423–3427. https://doi.org/10.1002/anie.201108118
62. Yamagata K, Goto Y, Nishimasu H et al (2014) Structural basis for potent inhibition of
SIRT2 deacetylase by a macrocyclic peptide inducing dynamic structural change. Structure 22
(2):345–352. https://doi.org/10.1016/j.str.2013.12.001
63. Asaba T, Suzuki T, Ueda R et al (2009) Inhibition of human sirtuins by in situ generation of an
acetylated lysine-ADP-ribose conjugate. J Am Chem Soc 131(20):6989–6996. https://doi.org/
10.1021/ja807083y
64. Suzuki T, Asaba T, Imai E et al (2009b) Identification of a cell-active non-peptide sirtuin
inhibitor containing N-thioacetyl lysine. Bioorg Med Chem Lett 19(19):5670–5672. https://
doi.org/10.1016/j.bmcl.2009.08.028
65. Jing H, Hu J, He B et al (2016) A SIRT2-selective inhibitor promotes c-Myc oncoprotein
degradation and exhibits broad anticancer activity. Cancer Cell 29(3):297–310. https://doi.org/
10.1016/j.ccell.2016.02.007
66. Huhtiniemi T, Salo HS, Suuronen T et al (2011) Structure-based design of pseudopeptidic
inhibitors for SIRT1 and SIRT2. J Med Chem 54(19):6456–6468. https://doi.org/10.1021/
jm200590k
67. Mellini P, Kokkola T, Suuronen T et al (2013) Screen of pseudopeptidic inhibitors of human
sirtuins 1-3: two lead compounds with antiproliferative effects in cancer cells. J Med Chem
56(17):6681–6695. https://doi.org/10.1021/jm400438k
68. He B, Du J, Lin H (2012) Thiosuccinyl peptides as Sirt5-specific inhibitors. J Am Chem Soc
134(4):1992–1995. https://doi.org/10.1021/ja2090417
69. Roessler C, Nowak T, Pannek M et al (2014) Chemical probing of the human sirtuin 5 active
site reveals its substrate acyl specificity and peptide-based inhibitors. Angew Chem Int Ed
Engl 53(40):10728–10732. https://doi.org/10.1002/anie.201402679
70. Zang W, Hao Y, Wang Z et al (2015) Novel thiourea-based sirtuin inhibitory warheads. Bioorg
Med Chem Lett 25(16):3319–3324. https://doi.org/10.1016/j.bmcl.2015.05.058
71. Liu J, Huang Y, Zheng W (2016) A selective cyclic peptidic human SIRT5 inhibitor.
Molecules 21(9):1217. https://doi.org/10.3390/molecules21091217
72. Wang J, Zang W, Liu J et al (2017) Bivalent SIRT1 inhibitors. Bioorg Med Chem Lett
27(2):180–186. https://doi.org/10.1016/j.bmcl.2016.11.082
73. Li L, Wang L, Li L et al (2012) Activation of p53 by SIRT1 inhibition enhances elimination of
CML leukemia stem cells in combination with imatinib. Cancer Cell 21(2):266–281. https://
doi.org/10.1016/j.ccr.2011.12.020
74. Ng FW, Wijaya L, Tang BL (2015) SIRT1 in the brain-connections with aging-associated
disorders and lifespan. Front Cell Neurosci 9:64. https://doi.org/10.3389/fncel.2015.00064
75. Parenti MD, Grozio A, Bauer I et al (2014) Discovery of novel and selective SIRT6 inhibitors.
J Med Chem 57(11):4796–4804. https://doi.org/10.1021/jm500487d
76. Rahnasto-Rilla M, Tyni J, Huovinen M et al (2018) Natural polyphenols as sirtuin 6 modulators. Sci Rep 8(1):4163. https://doi.org/10.1038/s41598-018-22388-5
77. Kim JH, Kim D, Cho SJ et al (2018) Identification of a novel SIRT7 inhibitor as anticancer
drug candidate. Biochem Biophys Res Commun 508(2):451–457. https://doi.org/10.1016/j.
bbrc.2018.11.120
Sirtuin Inhibitors and Activators
85