2.3 Small Molecule Inhibitors
Since 2001, a series of small molecular sirtuin inhibitors have been developed that
can be classified based on their scaffolds as β-naphthols, indoles, chromanones,
sulfobenzoic acid, or others. SIRT1 has been the most widely studied of the sirtuins
mainly because it was the first sirtuin linked with aging-associated disorders [10, 13,
73, 74]. The predominance of SIRT1 is also partly attributable to the fact that
initially small-molecule inhibitors were tested only for SIRT1 and SIRT2. The
importance of other sirtuins increased with time, and today, compounds inhibiting
the other sirtuins have been examined, especially those binding to SIRT3 and
SIRT5. Currently, the design of sirtuin inhibitors has focused more on identifying
selective SIRT2 inhibitors, and several of them have been published since 2012. A
few inhibitors have been developed for SIRT6 [59, 75, 76] and SIRT7 [77]. For
SIRT4 there are no compounds yet reported to have an IC 50 value.
2.3.1 β-Naphthol Derivatives
Sirtinol was one of the first identified sirtuin inhibitors (compound 19 in Fig. 4);
it showed inhibitory activity in vitro toward both yeast Sir2 (IC 50 ¼ 68 μM) and
human various sirtuins [78–80]. It was observed that the 2-hydroxyl-1-napthol
scaffold was essential for preventing the deacetylation reaction of sirtuins [78].
Later, the inhibitory activity of sirtinol was reported to lie in a range of IC 50 values
of 37–131 μM for SIRT1 and a range of IC 50 values of 38–58 μM for SIRT2 and at
IC 50 value of 48.9 μM for SIRT5 [80]. In addition, several analogs of sirtinol have
been designed. M15, another β-naphthol derivative, was synthesized, but it was less
potent than sirtinol. A set of ortho- to meta- or para-substitution derivatives of
sirtinol exhibited two to tenfold improvements in the SIRT1 and SIRT2 inhibition
activity [79]. Interestingly, some of these compounds also exhibited anticancer
activity [81, 82].
Modifications of sirtinol were used to identify a novel potent SIRT1 inhibitor,
JGB-1741 (compound 20 in Fig. 4), that consists of a hydroxyl-naphthol moiety and
a thiophene ring. JGB-1741 had an IC 50 value of 15 μM for SIRT1, whereas it was a
weak inhibitor for SIRT2 and SIRT3. JGB-1741 was observed to influence the
proliferation of human cancer cells (K562, HepG2, and MDA-MB-231), to increase
p53 acetylation, and to induce p53-mediated apoptosis in human breast cancer
cells [83].
Salermide (compound 21 in Fig. 4) was designed as analog of sirtinol, with a
reverse amide in the meta-position, and it showed SIRT2 inhibition with an IC 50
value of 25 μM. Salermide was nontoxic to mice, and it induced apoptosis in several
cancer cells [82, 84–86]. Salermide showed SIRT2 inhibition with an IC 50 value of
25 μM. Further modifications of Salermide led to the development of several potent
SIRT1 and SIRT2 inhibitors. The most potent inhibitor of these derivatives was
4-(2-phenylpropyl)thio-derivative (compound 22 in Fig. 4). This derivative of
64
M. Rahnasto-Rilla et al.
Since 2001, a series of small molecular sirtuin inhibitors have been developed that
can be classified based on their scaffolds as β-naphthols, indoles, chromanones,
sulfobenzoic acid, or others. SIRT1 has been the most widely studied of the sirtuins
mainly because it was the first sirtuin linked with aging-associated disorders [10, 13,
73, 74]. The predominance of SIRT1 is also partly attributable to the fact that
initially small-molecule inhibitors were tested only for SIRT1 and SIRT2. The
importance of other sirtuins increased with time, and today, compounds inhibiting
the other sirtuins have been examined, especially those binding to SIRT3 and
SIRT5. Currently, the design of sirtuin inhibitors has focused more on identifying
selective SIRT2 inhibitors, and several of them have been published since 2012. A
few inhibitors have been developed for SIRT6 [59, 75, 76] and SIRT7 [77]. For
SIRT4 there are no compounds yet reported to have an IC 50 value.
2.3.1 β-Naphthol Derivatives
Sirtinol was one of the first identified sirtuin inhibitors (compound 19 in Fig. 4);
it showed inhibitory activity in vitro toward both yeast Sir2 (IC 50 ¼ 68 μM) and
human various sirtuins [78–80]. It was observed that the 2-hydroxyl-1-napthol
scaffold was essential for preventing the deacetylation reaction of sirtuins [78].
Later, the inhibitory activity of sirtinol was reported to lie in a range of IC 50 values
of 37–131 μM for SIRT1 and a range of IC 50 values of 38–58 μM for SIRT2 and at
IC 50 value of 48.9 μM for SIRT5 [80]. In addition, several analogs of sirtinol have
been designed. M15, another β-naphthol derivative, was synthesized, but it was less
potent than sirtinol. A set of ortho- to meta- or para-substitution derivatives of
sirtinol exhibited two to tenfold improvements in the SIRT1 and SIRT2 inhibition
activity [79]. Interestingly, some of these compounds also exhibited anticancer
activity [81, 82].
Modifications of sirtinol were used to identify a novel potent SIRT1 inhibitor,
JGB-1741 (compound 20 in Fig. 4), that consists of a hydroxyl-naphthol moiety and
a thiophene ring. JGB-1741 had an IC 50 value of 15 μM for SIRT1, whereas it was a
weak inhibitor for SIRT2 and SIRT3. JGB-1741 was observed to influence the
proliferation of human cancer cells (K562, HepG2, and MDA-MB-231), to increase
p53 acetylation, and to induce p53-mediated apoptosis in human breast cancer
cells [83].
Salermide (compound 21 in Fig. 4) was designed as analog of sirtinol, with a
reverse amide in the meta-position, and it showed SIRT2 inhibition with an IC 50
value of 25 μM. Salermide was nontoxic to mice, and it induced apoptosis in several
cancer cells [82, 84–86]. Salermide showed SIRT2 inhibition with an IC 50 value of
25 μM. Further modifications of Salermide led to the development of several potent
SIRT1 and SIRT2 inhibitors. The most potent inhibitor of these derivatives was
4-(2-phenylpropyl)thio-derivative (compound 22 in Fig. 4). This derivative of
64
M. Rahnasto-Rilla et al.