content, inhibited the formation of reactive oxygen species (ROS), and enhanced the
activity of a mitochondria-localized antioxidant enzyme, manganese superoxide
dismutase (Mn-SOD) [183]. Although many studies have revealed that SIRT1
stimulates the expression of Mn-SOD [184–186], interestingly, the catalytic activity
of enzyme is regulated by SIRT3-mediated deacetylation, particularly at the Lys68
site [187]. The lignan honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2enyl-phenol), a natural biphenolic compound derived from the bark of magnolia
trees, has been demonstrated to activate SIRT3-dependent deacetylation of MnSOD
in vitro as well as enhancing SIRT3 expression in cardiomyocytes [188]. In addition,
SIRT3 activator, 7-hydroxy-3-(4
0 -methoxyphenyl) coumarin, promoted the
deacetylation and activation of Mn-SOD [189]. The increased activation of SIRT3
was associated with reduced ROS levels in cardiomyocytes obtained from wild-type
mice [188]. Phlorotannin- and fucoidan-rich extracts, from brown macroalgae,
namely, Fucus distichus, Fucus vesiculosus, and Cystoseira tamariscifolia, have
demonstrated significant activation toward SIRT6. Subsequently the isolated compound fucoidan from F. dichitus was observed to stimulate deacetylation activity.
The results suggest that the effect was SIRT6 specific and fucoidan did not exert
any effects on either SIRT1 or SIRT3 but displayed weak inhibition towards
SIRT2 [190].
3.2 Various Scaffolds of Sirtuin Activators
3.2.1 Imidazothiazoles
The first synthetic sirtuin activators, imidazothiazole derivatives, were chemically
distinct from the polyphenol backbone of resveratrol but demonstrated to activate
SIRT1 via the same K m -lowering mechanism [171]. The experiment was carried
out using a fluorescence polarization assay with a carboxytetramethylrhodamine
(TAMRA)-tagged substrate and verified using mass spectrometry. The potent activators, SRT1460 and SRT1720 (compound 59 in Fig. 13), displayed EC 50 values of
2.9 μM and 0.16 μM toward SIRT1, respectively. The activation by these compounds was selective versus SIRT2 and SIRT3 (SIRT2: SRT1460 EC 50 > 300 μM,
SRT1720 EC 50 ¼ 37 μM; SIRT3: EC 50 > 300 μM). SRT1720 has been widely
studied in various disease models such as type 2 diabetes, inflammation, and fatty
liver disease. SRT1720 treatment has shown beneficial metabolic effects by reducing
the blood glucose level and improving insulin sensitivity and glucose tolerance. It
was able to reduce lipid accumulation in the liver. SRT1720 has displayed antiinflammatory, anticancer, and cardioprotective properties [171].
Series of other synthetic compounds including thiazolopyridines (STAC-2)
(compound 60 in Fig. 13), benzimidazoles (STAC-5) (compound 61 in Fig. 13),
and bridged ureas (STAC-9) activated also SIRT1 [166, 169]. Synthetic compounds
increased SIRT1 deacetylation when an AMC-tagged peptide was used as the
substrate. However, it was demonstrated that the fluorescent moiety on substrates
Sirtuin Inhibitors and Activators
79
activity of a mitochondria-localized antioxidant enzyme, manganese superoxide
dismutase (Mn-SOD) [183]. Although many studies have revealed that SIRT1
stimulates the expression of Mn-SOD [184–186], interestingly, the catalytic activity
of enzyme is regulated by SIRT3-mediated deacetylation, particularly at the Lys68
site [187]. The lignan honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2enyl-phenol), a natural biphenolic compound derived from the bark of magnolia
trees, has been demonstrated to activate SIRT3-dependent deacetylation of MnSOD
in vitro as well as enhancing SIRT3 expression in cardiomyocytes [188]. In addition,
SIRT3 activator, 7-hydroxy-3-(4
0 -methoxyphenyl) coumarin, promoted the
deacetylation and activation of Mn-SOD [189]. The increased activation of SIRT3
was associated with reduced ROS levels in cardiomyocytes obtained from wild-type
mice [188]. Phlorotannin- and fucoidan-rich extracts, from brown macroalgae,
namely, Fucus distichus, Fucus vesiculosus, and Cystoseira tamariscifolia, have
demonstrated significant activation toward SIRT6. Subsequently the isolated compound fucoidan from F. dichitus was observed to stimulate deacetylation activity.
The results suggest that the effect was SIRT6 specific and fucoidan did not exert
any effects on either SIRT1 or SIRT3 but displayed weak inhibition towards
SIRT2 [190].
3.2 Various Scaffolds of Sirtuin Activators
3.2.1 Imidazothiazoles
The first synthetic sirtuin activators, imidazothiazole derivatives, were chemically
distinct from the polyphenol backbone of resveratrol but demonstrated to activate
SIRT1 via the same K m -lowering mechanism [171]. The experiment was carried
out using a fluorescence polarization assay with a carboxytetramethylrhodamine
(TAMRA)-tagged substrate and verified using mass spectrometry. The potent activators, SRT1460 and SRT1720 (compound 59 in Fig. 13), displayed EC 50 values of
2.9 μM and 0.16 μM toward SIRT1, respectively. The activation by these compounds was selective versus SIRT2 and SIRT3 (SIRT2: SRT1460 EC 50 > 300 μM,
SRT1720 EC 50 ¼ 37 μM; SIRT3: EC 50 > 300 μM). SRT1720 has been widely
studied in various disease models such as type 2 diabetes, inflammation, and fatty
liver disease. SRT1720 treatment has shown beneficial metabolic effects by reducing
the blood glucose level and improving insulin sensitivity and glucose tolerance. It
was able to reduce lipid accumulation in the liver. SRT1720 has displayed antiinflammatory, anticancer, and cardioprotective properties [171].
Series of other synthetic compounds including thiazolopyridines (STAC-2)
(compound 60 in Fig. 13), benzimidazoles (STAC-5) (compound 61 in Fig. 13),
and bridged ureas (STAC-9) activated also SIRT1 [166, 169]. Synthetic compounds
increased SIRT1 deacetylation when an AMC-tagged peptide was used as the
substrate. However, it was demonstrated that the fluorescent moiety on substrates
Sirtuin Inhibitors and Activators
79