[117]. One indole derivative, GW5074 (3-(3,5-dibromo-4-hydroxybenzylidene)-5iodo-1,3-dihydroindol-2-one), was reported to be a potent inhibitor of the
desuccinylation reaction of SIRT5 (IC 50 ¼ 19.5 μM) but not against deacetylation
reaction [113].
2.3.3 Chromanone and Chroman Derivatives as SIRT2 Inhibitors
A3 (compound 36 in Fig. 7) was discovered by phenotypic screening already in the
year 2001. A3 inhibited in vitro yeast Sir2p and human SIRT2 deacetylase activity
with IC 50 values of 66 μM and 45 μM, respectively [78]. Several chromanone
derivatives were developed and reported as selective and potent SIRT2 inhibitors.
The most potent compound, (S)-8-bromo-6-chloro-2-pentylchroman-4-one, displayed
SIRT2 inhibition with IC 50 value of 1.5 μM (compound 37 Fig. 7). Compound 37 did
not exhibit any inhibitory activity against SIRT1 and SIRT3 [118].
Although compound 37 was potent and selective for SIRT2 over SIRT1, it had
poor solubility, and thus a series of analogs were developed. These analogs
displayed low micromolar potency similar to that of compound 37. Two analogs
showed an antiproliferative effect in human breast cancer (MCF7) and in human
lung cancer (A549) cell lines [119]. Recently, the binding of chroman-4-one derivatives (compound 38 in Fig. 7) to SIRT2 was explored by a photoaffinity labeling
technique [120].
Various 2,2-dimethylchroman derivatives exhibited an antiproliferative effect in
glioma cells. One of the antiproliferative agents, compound 39 (Fig. 7), was also a
potent SIRT1 inhibitor (IC 50 ¼ 6.1 μM) and SIRT2 inhibitor (IC 50 ¼ 4.2 μM). This
O
O
O
HO
HO
A3 (36)
O
CH 3
Cl
O
SIRT2: 45 μΜ
(S)-8-bromo-6-chloro-2-pentylchroman-4-one (37)
SIRT2: 1.5 μΜ
O
Cl
O
N
Chroman-4-one derivative (38)
SIRT2: 3.7 μΜ
O
HN
HN
O
H
N
O
H 3 C
H 3 C CH 3 O
N
R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea (39)
SIRT1: 6.1 μΜ
SIRT2: 4.2 μΜ
Br
Br
Fig. 7 The structures of chromanone and chroman derived sirtuin inhibitors and their IC 50 values
Sirtuin Inhibitors and Activators
69
desuccinylation reaction of SIRT5 (IC 50 ¼ 19.5 μM) but not against deacetylation
reaction [113].
2.3.3 Chromanone and Chroman Derivatives as SIRT2 Inhibitors
A3 (compound 36 in Fig. 7) was discovered by phenotypic screening already in the
year 2001. A3 inhibited in vitro yeast Sir2p and human SIRT2 deacetylase activity
with IC 50 values of 66 μM and 45 μM, respectively [78]. Several chromanone
derivatives were developed and reported as selective and potent SIRT2 inhibitors.
The most potent compound, (S)-8-bromo-6-chloro-2-pentylchroman-4-one, displayed
SIRT2 inhibition with IC 50 value of 1.5 μM (compound 37 Fig. 7). Compound 37 did
not exhibit any inhibitory activity against SIRT1 and SIRT3 [118].
Although compound 37 was potent and selective for SIRT2 over SIRT1, it had
poor solubility, and thus a series of analogs were developed. These analogs
displayed low micromolar potency similar to that of compound 37. Two analogs
showed an antiproliferative effect in human breast cancer (MCF7) and in human
lung cancer (A549) cell lines [119]. Recently, the binding of chroman-4-one derivatives (compound 38 in Fig. 7) to SIRT2 was explored by a photoaffinity labeling
technique [120].
Various 2,2-dimethylchroman derivatives exhibited an antiproliferative effect in
glioma cells. One of the antiproliferative agents, compound 39 (Fig. 7), was also a
potent SIRT1 inhibitor (IC 50 ¼ 6.1 μM) and SIRT2 inhibitor (IC 50 ¼ 4.2 μM). This
O
O
O
HO
HO
A3 (36)
O
CH 3
Cl
O
SIRT2: 45 μΜ
(S)-8-bromo-6-chloro-2-pentylchroman-4-one (37)
SIRT2: 1.5 μΜ
O
Cl
O
N
Chroman-4-one derivative (38)
SIRT2: 3.7 μΜ
O
HN
HN
O
H
N
O
H 3 C
H 3 C CH 3 O
N
R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea (39)
SIRT1: 6.1 μΜ
SIRT2: 4.2 μΜ
Br
Br
Fig. 7 The structures of chromanone and chroman derived sirtuin inhibitors and their IC 50 values
Sirtuin Inhibitors and Activators
69