5-nitro-8-R-quinoline have also been proposed as potential treatments for HD. The
most potent compound, MIND4 (compound 46 in Fig. 10), displayed SIRT2 inhibitory activity with an IC 50 value of 1.2 μM. It displayed some neuroprotective
activity both in ex vivo brain slices and in Drosophila models of HD [137].
2.3.6 Various Small Molecules with Inhibitory Activities Towards
Sirtuins
Suramin is an old drug that was discovered to be a potent SIRT1 inhibitor
[138]. Suramin is a G-protein antagonist known to target purine binding sites, and
it was originally used in the treatment of trypanosomiasis and onchocerciasis.
Suramin exhibited IC 50 values of 297 μM, 1.2 μM, and 22 μM for SIRT1, SIRT2,
and SIRT5, respectively. Various suramin analogs have been synthetized with the
most potent suramin derivative having an IC 50 value of 93 nM for SIRT1 and
exhibiting selectivity over SIRT2 (IC 50 ¼ 2.3 μM) [139].
N,N
0 -Bisbenzylidenebenzene-1,4-diamines and N,N
0 -bisbenzylidenenaphthalene1,4-diamines were identified as sirtuin inhibitors from a virtual screening campaign
conducted by Tervo et al. [140]. The most potent compound exhibited inhibition
with an IC 50 value of 58 μM for SIRT2 [141]. Glycine tryptamide was also identified
by virtual screening [45]. This scaffold proved to be a starting structure for developing a novel series of sirtuin inhibitors; the best of these SIRT1 inhibitors had an
IC 50 value of 52 μM, and the best SIRT2 inhibitor had an IC 50 value of 47 μM [142].
A virtual screening identified an oxadiazole-carbonylaminothiourea to be a sirtuin
inhibitor. The hit compound displayed a preference toward SIRT2 over SIRT1 with
N
N
H
O
CN
O
Cl
Cl
SIRT1: > 50
SIRT2: 3.5
SIRT3: > 50
N
H
O
S
O O
N
AK-7 (45)
N
H
O
S
Br
O O
N
N
+
O
O
-
AK-1 (44)
SIRT1: >300
SIRT2: 15.5
SIRT3: >300
AGK2 (43)
N
N
N
O
S
N
N
+
O
- O
SIRT2: 12.5
SIRT2: 1.2
MIND4 (46)
Br
Fig. 10 The structures of AGK2 and sulfobenzoic acid-based sirtuin inhibitors and their IC 50
values
72
M. Rahnasto-Rilla et al.
most potent compound, MIND4 (compound 46 in Fig. 10), displayed SIRT2 inhibitory activity with an IC 50 value of 1.2 μM. It displayed some neuroprotective
activity both in ex vivo brain slices and in Drosophila models of HD [137].
2.3.6 Various Small Molecules with Inhibitory Activities Towards
Sirtuins
Suramin is an old drug that was discovered to be a potent SIRT1 inhibitor
[138]. Suramin is a G-protein antagonist known to target purine binding sites, and
it was originally used in the treatment of trypanosomiasis and onchocerciasis.
Suramin exhibited IC 50 values of 297 μM, 1.2 μM, and 22 μM for SIRT1, SIRT2,
and SIRT5, respectively. Various suramin analogs have been synthetized with the
most potent suramin derivative having an IC 50 value of 93 nM for SIRT1 and
exhibiting selectivity over SIRT2 (IC 50 ¼ 2.3 μM) [139].
N,N
0 -Bisbenzylidenebenzene-1,4-diamines and N,N
0 -bisbenzylidenenaphthalene1,4-diamines were identified as sirtuin inhibitors from a virtual screening campaign
conducted by Tervo et al. [140]. The most potent compound exhibited inhibition
with an IC 50 value of 58 μM for SIRT2 [141]. Glycine tryptamide was also identified
by virtual screening [45]. This scaffold proved to be a starting structure for developing a novel series of sirtuin inhibitors; the best of these SIRT1 inhibitors had an
IC 50 value of 52 μM, and the best SIRT2 inhibitor had an IC 50 value of 47 μM [142].
A virtual screening identified an oxadiazole-carbonylaminothiourea to be a sirtuin
inhibitor. The hit compound displayed a preference toward SIRT2 over SIRT1 with
N
N
H
O
CN
O
Cl
Cl
SIRT1: > 50
SIRT2: 3.5
SIRT3: > 50
N
H
O
S
O O
N
AK-7 (45)
N
H
O
S
Br
O O
N
N
+
O
O
-
AK-1 (44)
SIRT1: >300
SIRT2: 15.5
SIRT3: >300
AGK2 (43)
N
N
N
O
S
N
N
+
O
- O
SIRT2: 12.5
SIRT2: 1.2
MIND4 (46)
Br
Fig. 10 The structures of AGK2 and sulfobenzoic acid-based sirtuin inhibitors and their IC 50
values
72
M. Rahnasto-Rilla et al.