IC 50 values of 192 μM and 57 μM for SIRT1 and SIRT2, respectively. Various
substituents with an oxadiazole moiety were evaluated, and a low micromolar
SIRT1 inhibitor was developed. The study also revealed that the oxadiazolecarbonylaminothiourea scaffold was more potent than an oxadiazolecarbonylaminourea scaffold, similar to the case of thioacetylated peptides and
acetylated peptides [143]. Recently, a set of oxadiazole analogs has been designed
as selective SIRT2 inhibitors with IC 50 values in the range of 1.5–20 μM. Two of
these analogs displayed antiproliferative effects in leukemia cell lines. Kinetic
studies suggested that oxadiazole analogs were uncompetitive inhibitors. The crystal
structure of SIRT2 with one of the analogs has been published [144].
Tenovin-1 and Tenovin-6 were identified in a cell-based screening. Tenovin-1
had problems with solubility, but Tenovin-6 was sixfold more water soluble than
Tenovin-1. Tenovin-6 (compound 47 in Fig. 11) showed an IC 50 value of 21 μM for
SIRT1 and an IC 50 value of 10 μM for SIRT2, but it was slightly less potent toward
SIRT3. Tenovin-6 decreased tumor growth in vivo [145]. There are also reports that
Tenovin-6 was able to prevent cell proliferation in chronic myeloid leukemia cells
and an acute promyelocytic leukemia (NB4) cell line [73, 146]. Tenovin-6 has
exhibited antitumor effects in various cancer cell lines such as gastric and uveal
melanoma cells [147–149]. Tenovin-6 also displayed an antineoplastic effect in vitro
and in vivo on various hematopoietic malignancies [150, 151]. A set of analogs of
Tenovin-1 and Tenovin-6 was synthetized by adding various substituents with
different sizes and electronic properties in the tert-butyl-substituted aromatic ring
[152, 153]. The most potent analog was Tenovin-D3 (compound 48 in Fig. 11) with
IC 50 values of 22 μM for SIRT2 and >90 μM for SIRT1 [154].
The thieno[3,2-d]pyrimidine-6-carboxamide scaffold was discovered by screening a 1.2 million compound library using Encoded Library Technology. Several
potent SIRT1/SIRT2/SIRT3 inhibitors were identified with a nanomolar level inhibition for sirtuins. Compound 49 in Fig. 11 is an example of a carboxamide-based
sirtuin inhibitor, showing equal potency for SIRT1, SIRT2, and SIRT3. The crystal
structure was examined; this revealed that thieno[3,2-d]pyrimidine-6-carboxamides
(Fig. 12) bound onto the site of the nicotinamide moiety [155].
Various benzimidazole derivatives were synthesized and their SIRT1 and SIRT2
inhibitory activities were evaluated. The most potent compound exhibited an IC 50
value of 27 μM for SIRT2 and 52 μM for SIRT1. The compound showed also
anticancer activity against different cancer cell lines, i.e., colon (HCT-116), breast
(MDA-MB-468), and blood-leukemia (CCRF-CEM) [156].
Based on pharmacophore screening, ICL-SIRT078 (compound 50 in Fig. 11) was
identified as a potent SIRT2 inhibitor with IC 50 value of 0.17–3.96 μM. The
compound showed no activity toward SIRT1, SIRT3, or SIRT5. Interestingly, the
compound exerted a neuroprotective effect in a PD model. A series of analogs was
prepared with some of them displaying inhibitory activity in a range of 1.90 μM and
6.52 μM [157].
SIRT3 isoform-selective inhibitor, SDX437 (compound 51 in Fig. 11), was
screened from a 100,000 diverse compound library by using a novel substrate
GYK(Ac)RGC developed during the study. Several of the hit compounds inhibited
Sirtuin Inhibitors and Activators
73
substituents with an oxadiazole moiety were evaluated, and a low micromolar
SIRT1 inhibitor was developed. The study also revealed that the oxadiazolecarbonylaminothiourea scaffold was more potent than an oxadiazolecarbonylaminourea scaffold, similar to the case of thioacetylated peptides and
acetylated peptides [143]. Recently, a set of oxadiazole analogs has been designed
as selective SIRT2 inhibitors with IC 50 values in the range of 1.5–20 μM. Two of
these analogs displayed antiproliferative effects in leukemia cell lines. Kinetic
studies suggested that oxadiazole analogs were uncompetitive inhibitors. The crystal
structure of SIRT2 with one of the analogs has been published [144].
Tenovin-1 and Tenovin-6 were identified in a cell-based screening. Tenovin-1
had problems with solubility, but Tenovin-6 was sixfold more water soluble than
Tenovin-1. Tenovin-6 (compound 47 in Fig. 11) showed an IC 50 value of 21 μM for
SIRT1 and an IC 50 value of 10 μM for SIRT2, but it was slightly less potent toward
SIRT3. Tenovin-6 decreased tumor growth in vivo [145]. There are also reports that
Tenovin-6 was able to prevent cell proliferation in chronic myeloid leukemia cells
and an acute promyelocytic leukemia (NB4) cell line [73, 146]. Tenovin-6 has
exhibited antitumor effects in various cancer cell lines such as gastric and uveal
melanoma cells [147–149]. Tenovin-6 also displayed an antineoplastic effect in vitro
and in vivo on various hematopoietic malignancies [150, 151]. A set of analogs of
Tenovin-1 and Tenovin-6 was synthetized by adding various substituents with
different sizes and electronic properties in the tert-butyl-substituted aromatic ring
[152, 153]. The most potent analog was Tenovin-D3 (compound 48 in Fig. 11) with
IC 50 values of 22 μM for SIRT2 and >90 μM for SIRT1 [154].
The thieno[3,2-d]pyrimidine-6-carboxamide scaffold was discovered by screening a 1.2 million compound library using Encoded Library Technology. Several
potent SIRT1/SIRT2/SIRT3 inhibitors were identified with a nanomolar level inhibition for sirtuins. Compound 49 in Fig. 11 is an example of a carboxamide-based
sirtuin inhibitor, showing equal potency for SIRT1, SIRT2, and SIRT3. The crystal
structure was examined; this revealed that thieno[3,2-d]pyrimidine-6-carboxamides
(Fig. 12) bound onto the site of the nicotinamide moiety [155].
Various benzimidazole derivatives were synthesized and their SIRT1 and SIRT2
inhibitory activities were evaluated. The most potent compound exhibited an IC 50
value of 27 μM for SIRT2 and 52 μM for SIRT1. The compound showed also
anticancer activity against different cancer cell lines, i.e., colon (HCT-116), breast
(MDA-MB-468), and blood-leukemia (CCRF-CEM) [156].
Based on pharmacophore screening, ICL-SIRT078 (compound 50 in Fig. 11) was
identified as a potent SIRT2 inhibitor with IC 50 value of 0.17–3.96 μM. The
compound showed no activity toward SIRT1, SIRT3, or SIRT5. Interestingly, the
compound exerted a neuroprotective effect in a PD model. A series of analogs was
prepared with some of them displaying inhibitory activity in a range of 1.90 μM and
6.52 μM [157].
SIRT3 isoform-selective inhibitor, SDX437 (compound 51 in Fig. 11), was
screened from a 100,000 diverse compound library by using a novel substrate
GYK(Ac)RGC developed during the study. Several of the hit compounds inhibited
Sirtuin Inhibitors and Activators
73