decreased HIV transcription. Further modification of splitomicin analogs (e.g.,
compound 25 in Fig. 4) led to the discovery of novel human SIRT2 inhibitors
with IC 50 values in a range of 0.8–38 μM for SIRT2 [92, 93]. Some splitomicin
analogs exerted a weak antiproliferative effect in human breast cancer (MCF7) cells
[93], and splitomicin prevented inflammatory responses in human neutrophils [94].
Cambinol (compound 26 in Fig. 4) had a beta-naphthol moiety similar to that of
sirtinol and its derivatives. Cambinol inhibited both SIRT1 (IC 50 ¼ 56 μM) and
SIRT2 (IC 50 ¼ 59 μM) but showed no SIRT3 inhibition [95]. In later studies,
cambinol displayed IC 50 value of 43 μM also toward SIRT5 [80]. The β-naphthol
structure was reported to be critical for the inhibition and replacing it with a phenyl
ring abolished the activity. The kinetic studies showed that cambinol was a competitive inhibitor with the acetylated substrate but not with NAD
+
. Cambinol had low
toxicity in vivo, and cambinol was a potent antitumor agent in vitro and in vivo
[95]. Recently, cambinol was identified to be ten times more potent in inhibiting
neutral sphingomyelinase 2 in brain than its effects on either SIRT1 and SIRT2
[96]. In attempts to improve isoform-selectivity, a p-bromo-analog of cambinol was
designed; this was a very potent SIRT1 inhibitor with an IC 50 value of 13 μM, while
it exhibited only modest potency toward SIRT2 (IC 50 > 90 μM). Interestingly,
adding a substituent at the N1-position in cambinol derivative (compound 27 in
Fig. 4) led to an increase in the activity against SIRT2 (IC 50 ¼ 1 μM), and a decrease
in the inhibition against SIRT1 [97]. Other cambinol analogs were synthesized with
improved potencies and isoform-selectivities [98, 99]. These analogs exhibited some
cytotoxicity in cell lines derived from Burkitt’s lymphoma (Dakiki, Daudi, Mutu,
Oku, Ramos, Namalwa) and in colon (HCT116), breast (MCF7), and non-small cell
lung carcinoma (NCI-H460).
Various benzodeazaoxaflavin (compound 28 in Fig. 4) derivatives were
synthetized with low micromolar level potencies at inhibiting both SIRT1 and
SIRT2 [100, 101]. MC2141 exhibited antiproliferative activity in human cancer
cell lines (Raji, DLD1, and HeLa) as well as in cancer stem cells of colorectal
carcinoma and glioblastoma multiforme. Some analogs of MC2141 were designed
showing SIRT1 and SIRT2 inhibition with IC 50 values in the low micromolar range.
2.3.2 Indole Derivatives as Potent SIRT1 Inhibitors
A high-throughput screening (HTS) of 280,000 compounds led to the discovery of a
potent indole-based inhibitor, called Ex-527 [102]. Ex-527 (compound 29 in Fig. 6)
was a nanomolar inhibitor for SIRT1 (IC 50 ¼ 38–100 nM), and this was a 500-fold
improvement compared to other sirtuin inhibitors available at that time. Interestingly, the (S)-isomer was the active form, while the (R)-isomer had significantly
lower potency. In addition, this new indole compound showed isoform-selectivity
over SIRT2 and SIRT3 since their IC 50 values were in the micromolar range and
Ex-527 exerted no inhibition toward SIRT4–7 [102, 103]. This inspired the synthesis
of various analogs with an indole scaffold. SAR analysis of these compounds
revealed the necessity of carboxamide and its position for the inhibitory activity
66
M. Rahnasto-Rilla et al.
compound 25 in Fig. 4) led to the discovery of novel human SIRT2 inhibitors
with IC 50 values in a range of 0.8–38 μM for SIRT2 [92, 93]. Some splitomicin
analogs exerted a weak antiproliferative effect in human breast cancer (MCF7) cells
[93], and splitomicin prevented inflammatory responses in human neutrophils [94].
Cambinol (compound 26 in Fig. 4) had a beta-naphthol moiety similar to that of
sirtinol and its derivatives. Cambinol inhibited both SIRT1 (IC 50 ¼ 56 μM) and
SIRT2 (IC 50 ¼ 59 μM) but showed no SIRT3 inhibition [95]. In later studies,
cambinol displayed IC 50 value of 43 μM also toward SIRT5 [80]. The β-naphthol
structure was reported to be critical for the inhibition and replacing it with a phenyl
ring abolished the activity. The kinetic studies showed that cambinol was a competitive inhibitor with the acetylated substrate but not with NAD
+
. Cambinol had low
toxicity in vivo, and cambinol was a potent antitumor agent in vitro and in vivo
[95]. Recently, cambinol was identified to be ten times more potent in inhibiting
neutral sphingomyelinase 2 in brain than its effects on either SIRT1 and SIRT2
[96]. In attempts to improve isoform-selectivity, a p-bromo-analog of cambinol was
designed; this was a very potent SIRT1 inhibitor with an IC 50 value of 13 μM, while
it exhibited only modest potency toward SIRT2 (IC 50 > 90 μM). Interestingly,
adding a substituent at the N1-position in cambinol derivative (compound 27 in
Fig. 4) led to an increase in the activity against SIRT2 (IC 50 ¼ 1 μM), and a decrease
in the inhibition against SIRT1 [97]. Other cambinol analogs were synthesized with
improved potencies and isoform-selectivities [98, 99]. These analogs exhibited some
cytotoxicity in cell lines derived from Burkitt’s lymphoma (Dakiki, Daudi, Mutu,
Oku, Ramos, Namalwa) and in colon (HCT116), breast (MCF7), and non-small cell
lung carcinoma (NCI-H460).
Various benzodeazaoxaflavin (compound 28 in Fig. 4) derivatives were
synthetized with low micromolar level potencies at inhibiting both SIRT1 and
SIRT2 [100, 101]. MC2141 exhibited antiproliferative activity in human cancer
cell lines (Raji, DLD1, and HeLa) as well as in cancer stem cells of colorectal
carcinoma and glioblastoma multiforme. Some analogs of MC2141 were designed
showing SIRT1 and SIRT2 inhibition with IC 50 values in the low micromolar range.
2.3.2 Indole Derivatives as Potent SIRT1 Inhibitors
A high-throughput screening (HTS) of 280,000 compounds led to the discovery of a
potent indole-based inhibitor, called Ex-527 [102]. Ex-527 (compound 29 in Fig. 6)
was a nanomolar inhibitor for SIRT1 (IC 50 ¼ 38–100 nM), and this was a 500-fold
improvement compared to other sirtuin inhibitors available at that time. Interestingly, the (S)-isomer was the active form, while the (R)-isomer had significantly
lower potency. In addition, this new indole compound showed isoform-selectivity
over SIRT2 and SIRT3 since their IC 50 values were in the micromolar range and
Ex-527 exerted no inhibition toward SIRT4–7 [102, 103]. This inspired the synthesis
of various analogs with an indole scaffold. SAR analysis of these compounds
revealed the necessity of carboxamide and its position for the inhibitory activity
66
M. Rahnasto-Rilla et al.