was indeed unnecessary for activation since it could be replaced by hydrophobic
amino acids. In addition, specific hydrophobic motifs found in SIRT1 natural substrates such as peroxisome proliferator-activated receptor gamma coactivator
1-alpha (PGC-1α) and forkhead O transcription factor 3α (FOXO3α) were demonstrated to facilitate SIRT1 activation by all of the reported STACs compounds. Thus,
SIRT1 activation was demonstrated as a substrate-specific effect with certain native
sequences, while no effect or inhibition was observed with others [169].
3.2.2 Pyridine and Related Derivatives as Sirtuin Activators
One group of sirtuin activators, dihydropyridines (compound 62 in Fig. 13), with a
benzyl group at the N1 position displayed SIRT1 activation with EC 150 values (the
effective concentration which increases the enzyme activity to 150%) about 1 μM
but also a moderate activation for SIRT2 and SIRT3 with EC 150 values of 15 μM and
50 μM, respectively. Dihydropyridines with a carbethoxy (ester) or carboxy substitution at the 3,5 positions demonstrated the highest activating potencies against
SIRT1 when compared to the carboxamide moiety [170]. Valente et al. [191]
synthetized a series of dihydropyridine analogs, and the results demonstrated that
the replacement of the N1-benzyl moiety with the benzoyl portion, 2-pyrazinoyl, or
2-naphthoyl group led to higher SIRT1 activation. In addition, the substitution of the
C4-phenyl ring with mono- or bicyclic heteroaromatic rings increased potency
against SIRT1. Modified compounds displayed high nitric oxide (NO) release in
human keratinocyte (HaCat) cells and ameliorated skin repair in a mouse model of
wound healing [191]. NO release is involved in the maintenance of skin homeostasis
as well as in the modulation of inflammatory response.
Another group of pyridines, oxalopyridines (compound 63 in Fig. 13), showed
moderate activation of SIRT1 with EC 1.5 (the concentration of compound required
to increase the enzyme activity by 50%) in a range of 6–25 μM. Later, a set of
oxalopyridine analogs was synthetized, and the results revealed the importance of
the position of the substituents in the phenyl ring. Ortho-substitution in the central
phenyl ring gave the most potent activation, EC 1.5 ¼ 0.9 μM. By replacing the
bicyclic scaffold to a benzimidazole and its analog, even more potent SIRT1
activators were developed: benzimidazoles and azalbenzimidazoles exhibited
EC 1.5 values of 0.3 μM benzimidazole and 0.5 μM ¼ azalbenzimidasoles,
respectively [165].
3.2.3 Other Activators
Feldman et al. [42] reported the activation of SIRT6 by long-chain fatty acids. Free
long-chain fatty acids stimulated the deacetylation activity of SIRT6 by factors of
5.6 and 6.2 in the case of oleic and linoleic acid, respectively. Other fatty acids, such
as myristic, palmitic, stearic, γ-linolenic, and α-linolenic acids, showed activation
factors of 2.5–2.8. The activation mechanism was investigated by steady-state
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M. Rahnasto-Rilla et al.
amino acids. In addition, specific hydrophobic motifs found in SIRT1 natural substrates such as peroxisome proliferator-activated receptor gamma coactivator
1-alpha (PGC-1α) and forkhead O transcription factor 3α (FOXO3α) were demonstrated to facilitate SIRT1 activation by all of the reported STACs compounds. Thus,
SIRT1 activation was demonstrated as a substrate-specific effect with certain native
sequences, while no effect or inhibition was observed with others [169].
3.2.2 Pyridine and Related Derivatives as Sirtuin Activators
One group of sirtuin activators, dihydropyridines (compound 62 in Fig. 13), with a
benzyl group at the N1 position displayed SIRT1 activation with EC 150 values (the
effective concentration which increases the enzyme activity to 150%) about 1 μM
but also a moderate activation for SIRT2 and SIRT3 with EC 150 values of 15 μM and
50 μM, respectively. Dihydropyridines with a carbethoxy (ester) or carboxy substitution at the 3,5 positions demonstrated the highest activating potencies against
SIRT1 when compared to the carboxamide moiety [170]. Valente et al. [191]
synthetized a series of dihydropyridine analogs, and the results demonstrated that
the replacement of the N1-benzyl moiety with the benzoyl portion, 2-pyrazinoyl, or
2-naphthoyl group led to higher SIRT1 activation. In addition, the substitution of the
C4-phenyl ring with mono- or bicyclic heteroaromatic rings increased potency
against SIRT1. Modified compounds displayed high nitric oxide (NO) release in
human keratinocyte (HaCat) cells and ameliorated skin repair in a mouse model of
wound healing [191]. NO release is involved in the maintenance of skin homeostasis
as well as in the modulation of inflammatory response.
Another group of pyridines, oxalopyridines (compound 63 in Fig. 13), showed
moderate activation of SIRT1 with EC 1.5 (the concentration of compound required
to increase the enzyme activity by 50%) in a range of 6–25 μM. Later, a set of
oxalopyridine analogs was synthetized, and the results revealed the importance of
the position of the substituents in the phenyl ring. Ortho-substitution in the central
phenyl ring gave the most potent activation, EC 1.5 ¼ 0.9 μM. By replacing the
bicyclic scaffold to a benzimidazole and its analog, even more potent SIRT1
activators were developed: benzimidazoles and azalbenzimidazoles exhibited
EC 1.5 values of 0.3 μM benzimidazole and 0.5 μM ¼ azalbenzimidasoles,
respectively [165].
3.2.3 Other Activators
Feldman et al. [42] reported the activation of SIRT6 by long-chain fatty acids. Free
long-chain fatty acids stimulated the deacetylation activity of SIRT6 by factors of
5.6 and 6.2 in the case of oleic and linoleic acid, respectively. Other fatty acids, such
as myristic, palmitic, stearic, γ-linolenic, and α-linolenic acids, showed activation
factors of 2.5–2.8. The activation mechanism was investigated by steady-state
80
M. Rahnasto-Rilla et al.