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pp 1-38 | Cite as

Sirtuin Inhibitors and Activators

  • Minna Rahnasto-Rilla
  • Jonna Tyni
  • Maija Lahtela-Kakkonen
Chapter
Part of the Topics in Medicinal Chemistry book series

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 

Abbreviations

AD

Alzheimer’s disease

ADP

Adenosine diphosphate

AMC

7-Amino-4-methylcoumarin

ATP

Adenosine triphosphate

BIM

Bisindolylmaleimides

CPS1

Carbamoyl phosphate synthetase peptides

EC1.5

Concentration of compound required to increase the enzyme activity by 50%

EC150

Effective concentration which increases the enzyme activity to 150%

EC50

Half maximal effective concentration

FOXO3α

Forkhead O transcription factor 3 α

H3K9

Histone H3 lysine 9

HD

Huntington’s disease

HDAC

Histone deacetylase enzymes

HTS

High-throughput screening

IC50

Half maximal inhibitory concentration

ICL-SIRT078

3-((2-Methoxynaphthalen-1-yl)methyl)-7-((pyridin-3-ylmethyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one

Km

Value of substrate concentration at half maximal velocity

LPS

Lipopolysaccharides

Mn-SOD

Manganese superoxide dismutase

NAD+

Nicotinamide adenine dinucleotide

NAM

Nicotinamide

NO

Nitric oxide

PCK, PGC-1α

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha Protein kinase C

PD

Parkinson’s disease

ROS

Reactive oxygen species

SAR

Structure-activity relationships

SirReal2

Sirtuin-rearranging ligand2

SIRT

Sirtuins

SIRT1

Silent information regulator type 1

STACs

Sirtuin-activating compounds

TAMRA

Tetramethylrhodamine

TNFα

Tumor necrosis factor alpha

Notes

Compliance with Ethical Standards

Funding: M.R-R. was supported by Academy of Finland (grant no. 269341), Finnish Cultural Foundation, and Maud Kuistila Memorial Foundation. J.T was supported by UEF Doctoral School.

M.L-K. was supported by Academy of Finland (grant no 315824).

Conflict of Interest: There is no conflict of interest.

Ethical Approval: This chapter does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent: This chapter does not contain any informed consent material.

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Copyright information

© Springer Nature Switzerland AG  2019

Authors and Affiliations

  • Minna Rahnasto-Rilla
    • 1
  • Jonna Tyni
    • 1
  • Maija Lahtela-Kakkonen
    • 1
  1. 1.School of Pharmacy, University of Eastern FinlandKuopioFinland

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