Top Med Chem (2020) 33: 55–92
DOI: 10.1007/7355_2019_70
© Springer Nature Switzerland AG 2019
Published online: 30 October 2019
Sirtuin Inhibitors and Activators
Minna Rahnasto-Rilla, Jonna Tyni, and Maija Lahtela-Kakkonen
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2 Sirtuin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
2.1 Inhibitors Mimicking Substrates or Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
2.2 Substrate-Based Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.3 Small Molecule Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
3 Sirtuin Activators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.1 Natural Compounds Activating Sirtuins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.2 Various Scaffolds of Sirtuin Activators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4 General Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Abstract The mammalian family of sirtuins (SIRT1–7) target a large variety of
proteins at various subcellular localizations and thus exert regulatory effects on
critical biological processes such as gene silencing, DNA repair, and chromosomal
stability and longevity. Sirtuins play crucial roles in many signaling pathways and
are regarded as potential therapeutic targets in several pathological conditions,
such as cancer, metabolic disorders, and also cardiovascular and neurodegenerative
diseases. Therefore, the modulation of sirtuin activity by inhibitors or activators
could be beneficial for human health, a topic that has been interesting scientists for
over 15 years. Researchers have developed novel inhibitors and activators toward
sirtuins mainly for human silent information regulator type 1 (SIRT1) because both
cellular studies and experiments in animal models have indicated that SIRT1
regulators could be used for the treatment for multiple human diseases. Gradually,
an appreciation of the importance of the other members of the sirtuin family has
increased, and potent inhibitors and activators are designed for various sirtuins.
Keywords Activation, Deacetylation, Drug design and development, Inhibition,
Sirtuin
M. Rahnasto-Rilla, J. Tyni, and M. Lahtela-Kakkonen (*)
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
e-mail: maija.lahtela-kakkonen@uef.fi
DOI: 10.1007/7355_2019_70
© Springer Nature Switzerland AG 2019
Published online: 30 October 2019
Sirtuin Inhibitors and Activators
Minna Rahnasto-Rilla, Jonna Tyni, and Maija Lahtela-Kakkonen
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2 Sirtuin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
2.1 Inhibitors Mimicking Substrates or Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
2.2 Substrate-Based Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.3 Small Molecule Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
3 Sirtuin Activators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.1 Natural Compounds Activating Sirtuins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.2 Various Scaffolds of Sirtuin Activators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4 General Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Abstract The mammalian family of sirtuins (SIRT1–7) target a large variety of
proteins at various subcellular localizations and thus exert regulatory effects on
critical biological processes such as gene silencing, DNA repair, and chromosomal
stability and longevity. Sirtuins play crucial roles in many signaling pathways and
are regarded as potential therapeutic targets in several pathological conditions,
such as cancer, metabolic disorders, and also cardiovascular and neurodegenerative
diseases. Therefore, the modulation of sirtuin activity by inhibitors or activators
could be beneficial for human health, a topic that has been interesting scientists for
over 15 years. Researchers have developed novel inhibitors and activators toward
sirtuins mainly for human silent information regulator type 1 (SIRT1) because both
cellular studies and experiments in animal models have indicated that SIRT1
regulators could be used for the treatment for multiple human diseases. Gradually,
an appreciation of the importance of the other members of the sirtuin family has
increased, and potent inhibitors and activators are designed for various sirtuins.
Keywords Activation, Deacetylation, Drug design and development, Inhibition,
Sirtuin
M. Rahnasto-Rilla, J. Tyni, and M. Lahtela-Kakkonen (*)
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
e-mail: maija.lahtela-kakkonen@uef.fi