kinetic analyses, and the results suggested that myristic acid could stimulate the
deacetylase activity of SIRT6 by increasing the affinity of the enzyme for an
acetylated substrate by 35 times. A series of N-acylethanolamines also possessed
slightly increased SIRT6 activity, with oleoylethanolamide and myristoylethanolamide exhibiting maximal activation, i.e., a doubling [182].
Pyrroloquinoxalines (compound 64 in Fig. 13) were identified as SIRT1 activators displaying EC 50 values greater than 1 μM for SIRT1. These compounds
decreased lipopolysaccharides (LPS)-induced tumor necrosis factor-α (TNF-α) in
human THP-1 leukemia cells [192]. You and coworkers screened as SIRT6 activators a series of the pyrrolo[1,2-a]quinoxaline-based compounds [31]. The most
potent compound evoked a dose-dependent increase in SIRT6 activity, with a
maximum of twofold stimulation and an EC 50 value of 38 μM. Examination of
several X-ray structures with co-crystallized compounds has demonstrated that these
compounds bind predominantly through the C-pocket at the acyl channel.
4 General Conclusions
The sirtuins are a family of antiaging enzymes; they are some of the most promising
epigenetic targets in drug development for age-related diseases. The human
SIRT1–7 play important roles in numerous biological processes. They affect gene
transcription, tolerance to stress, adaptive mechanisms of metabolism, inflammatory
response, biological rhythms, and cellular senescence, to mention but a few. Human
SIRT1 has been one of the most intriguing research targets during the past years.
Gradually, the role of other members of the sirtuin family has increased, and it has
been speculated that modulation of these sirtuins could exert impacts on cancer,
inflammation, and cardiovascular and metabolic diseases.
The regulation of sirtuins has attracted significant research interest, and many
drug discovery research groups around the world have been searching for new sirtuin
regulators. A large number of new sirtuin inhibitors, belonging to various compound
classes, have been identified during the past years. In particular, compounds capable
of inhibiting the sirtuins are intriguing targets for neurodegenerative diseases and
cancer. There has been a special interest in developing sirtuin activators since they
might have beneficial impact on human health. Although a group of synthetic and
more potent activators has been described, there are still relatively few activators for
most of the sirtuins. Selective and potent sirtuin inhibitors and activators may be
beneficial in improving human health and combatting many diseases.
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.
Sirtuin Inhibitors and Activators
81
deacetylase activity of SIRT6 by increasing the affinity of the enzyme for an
acetylated substrate by 35 times. A series of N-acylethanolamines also possessed
slightly increased SIRT6 activity, with oleoylethanolamide and myristoylethanolamide exhibiting maximal activation, i.e., a doubling [182].
Pyrroloquinoxalines (compound 64 in Fig. 13) were identified as SIRT1 activators displaying EC 50 values greater than 1 μM for SIRT1. These compounds
decreased lipopolysaccharides (LPS)-induced tumor necrosis factor-α (TNF-α) in
human THP-1 leukemia cells [192]. You and coworkers screened as SIRT6 activators a series of the pyrrolo[1,2-a]quinoxaline-based compounds [31]. The most
potent compound evoked a dose-dependent increase in SIRT6 activity, with a
maximum of twofold stimulation and an EC 50 value of 38 μM. Examination of
several X-ray structures with co-crystallized compounds has demonstrated that these
compounds bind predominantly through the C-pocket at the acyl channel.
4 General Conclusions
The sirtuins are a family of antiaging enzymes; they are some of the most promising
epigenetic targets in drug development for age-related diseases. The human
SIRT1–7 play important roles in numerous biological processes. They affect gene
transcription, tolerance to stress, adaptive mechanisms of metabolism, inflammatory
response, biological rhythms, and cellular senescence, to mention but a few. Human
SIRT1 has been one of the most intriguing research targets during the past years.
Gradually, the role of other members of the sirtuin family has increased, and it has
been speculated that modulation of these sirtuins could exert impacts on cancer,
inflammation, and cardiovascular and metabolic diseases.
The regulation of sirtuins has attracted significant research interest, and many
drug discovery research groups around the world have been searching for new sirtuin
regulators. A large number of new sirtuin inhibitors, belonging to various compound
classes, have been identified during the past years. In particular, compounds capable
of inhibiting the sirtuins are intriguing targets for neurodegenerative diseases and
cancer. There has been a special interest in developing sirtuin activators since they
might have beneficial impact on human health. Although a group of synthetic and
more potent activators has been described, there are still relatively few activators for
most of the sirtuins. Selective and potent sirtuin inhibitors and activators may be
beneficial in improving human health and combatting many diseases.
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.
Sirtuin Inhibitors and Activators
81