since changing the carboxamide from 1-position to 2-position led to a 350-fold loss
in potency. The substitution of a small nonpolar group such as methyl at the paraposition and the expansion of the carbon 6-membered ring to a 7-membered ring
retained the inhibition potency. Kinetic studies suggested that Ex-527 was not a
competitive inhibitor with the substrate peptide or with NAD
+
. Ex-527 was postulated to bind to the protein after NAM release and potentially affects the release of
the reaction products. The crystal structure of Ex-527 bound with different sirtuins
revealed that Ex-527 was occupying the nicotinamide site and a pocket of the ribose
of NAD
+ (Fig. 5) [104, 105]. Ex-527 induced apoptosis in acute myeloid leukemia
via p53 [106]. In addition, Ex-527 was assessed as a potential HD therapy as it
suppressed the deacetylation of mutant huntingtin protein, i.e., it accelerated the
degradation of the acetylated mutant via autophagy [107]. Ex-527, also called
selisistat, passed through phase II clinical trials for the treatment of HD [108, 109].
Selisistat was also combined with carprofen, a known anti-inflammatory drug.
The most potent analog of this combination increased the acetyl-p53 and acetylalpha-tubulin levels and induced apoptosis in human macrophage (U937) cells
[110]. A few other indole derivatives were developed as sirtuin inhibitors (compound 30 in Fig. 6). One of these derivatives was called AC-93253 (compound
31 Fig. 6); this compound displayed low micromolar inhibition toward SIRT1,
SIRT2, and SIRT3. AC-93253 induced cytotoxicity in several cancer cell lines
(DU-145, A549, NCI-H460, MiaPaCa2, HuVEC, PrEC, HMEC) in the
submicromolar range [111]. In addition, 3-arylideneindolin-2-ones were identified
as novel sirtuin inhibitors. Among these compounds, GW5074 (compound 32 in
Fig. 6) was observed to be a potent inhibitor of various sirtuins [112, 113].
Inauhzin (compound 33 in Fig. 6) belongs to indole-based derivatives that
showed inhibitory activity toward SIRT1 with an IC 50 value ranging from 0.7 to
2 μM. Inauhzin evoked p53-dependent apoptosis of human cancer cells without
causing any apparently genotoxic stress [114]. Some indole derivatives were developed by combining an indole ring with a substituted triazole; they were found to be
Fig. 5 The crystal structure
of SIRT1 together with
inhibitor Ex-527 (blue) and
ribose-nicotinamide moiety
of NAD
+ (red) [104]. Active
histidine is marked with
black. Residues forming
interactions to Ex-527 are
marked with green color.
Green dashes indicate π-π
interactions
Sirtuin Inhibitors and Activators
67
in potency. The substitution of a small nonpolar group such as methyl at the paraposition and the expansion of the carbon 6-membered ring to a 7-membered ring
retained the inhibition potency. Kinetic studies suggested that Ex-527 was not a
competitive inhibitor with the substrate peptide or with NAD
+
. Ex-527 was postulated to bind to the protein after NAM release and potentially affects the release of
the reaction products. The crystal structure of Ex-527 bound with different sirtuins
revealed that Ex-527 was occupying the nicotinamide site and a pocket of the ribose
of NAD
+ (Fig. 5) [104, 105]. Ex-527 induced apoptosis in acute myeloid leukemia
via p53 [106]. In addition, Ex-527 was assessed as a potential HD therapy as it
suppressed the deacetylation of mutant huntingtin protein, i.e., it accelerated the
degradation of the acetylated mutant via autophagy [107]. Ex-527, also called
selisistat, passed through phase II clinical trials for the treatment of HD [108, 109].
Selisistat was also combined with carprofen, a known anti-inflammatory drug.
The most potent analog of this combination increased the acetyl-p53 and acetylalpha-tubulin levels and induced apoptosis in human macrophage (U937) cells
[110]. A few other indole derivatives were developed as sirtuin inhibitors (compound 30 in Fig. 6). One of these derivatives was called AC-93253 (compound
31 Fig. 6); this compound displayed low micromolar inhibition toward SIRT1,
SIRT2, and SIRT3. AC-93253 induced cytotoxicity in several cancer cell lines
(DU-145, A549, NCI-H460, MiaPaCa2, HuVEC, PrEC, HMEC) in the
submicromolar range [111]. In addition, 3-arylideneindolin-2-ones were identified
as novel sirtuin inhibitors. Among these compounds, GW5074 (compound 32 in
Fig. 6) was observed to be a potent inhibitor of various sirtuins [112, 113].
Inauhzin (compound 33 in Fig. 6) belongs to indole-based derivatives that
showed inhibitory activity toward SIRT1 with an IC 50 value ranging from 0.7 to
2 μM. Inauhzin evoked p53-dependent apoptosis of human cancer cells without
causing any apparently genotoxic stress [114]. Some indole derivatives were developed by combining an indole ring with a substituted triazole; they were found to be
Fig. 5 The crystal structure
of SIRT1 together with
inhibitor Ex-527 (blue) and
ribose-nicotinamide moiety
of NAD
+ (red) [104]. Active
histidine is marked with
black. Residues forming
interactions to Ex-527 are
marked with green color.
Green dashes indicate π-π
interactions
Sirtuin Inhibitors and Activators
67