Chemistry Reference
In-Depth Information
TABLE 13.1
Inhibition of Glycosidases by Triazoles
Enzyme
Compound
a
SAG (%)
ECG (%)
BLG (%)
58
<
20
30
±
11
<
20
59
<
20
<
20
48
±
11
DNJGal
<
20
91
±
1
<
20
DNJGluco
<
20
a
All compounds were screened at the concentration of 0.24 mM.
50
±
8
<
20
activity of
-GCase. Additionally, iminosugars containing hydrophobic groups may
act as chaperones to stabilize N370S
-GCase, the most common mutation causing
Gaucher disease. Based on these findings, 14 new hydrophobic iminosugars were
synthesized by coupling alkynyl-armed substituents to an azido-functionalized
N
-
propyl-DNJ core, using commercially available hydrophobic alkynes, in microwave
CuAAC-assisted reactions catalyzed by CuSO
4
/sodium ascorbate in a mixture of
dioxane-water (4:1) (Fig. 13.3) [44]. The triazole-iminosugars
64-77
were then tested
against a set of commercial glucosidase and
-GCase, besides mutant Gaucher lym-
phoblasts with the most common N370S mutation to assess their chaperone activity.
Most of the compounds showed inhibitory activity toward commercial
-glucosidase
(9 to 669
M from bovine liver and 0.59 to 177
M from almond), amyloglucosidase
(1 to
>
2 mM), and baker's yeast
-glucosidase (20
Mto
>
2 mM). As observed
for
-GCase was dis-
played by derivatives bearing hydrophobic
N
-substituents, such as compounds
66
,
67
,
71
and
72
, which were able to inhibit the enzyme in a range of 25-30% at 5
-glucosidases, the highest inhibitory potency toward N370S
M.
Regarding the chaperone activity in mutant Gaucher cells, even though compound
72
was the most active of the series, promoting a twofold increase in enzyme activity
at 20
M, no direct correlation was obtained for
-GCase and cellular chaperone
activities [44].
The regio- and stereocontrolled synthesis of novel non-fused 1,2,3-triazolo-
pseudooligosaccharides was carried out with the aim to improve acarbose activity, a
potent
-glucosidase inhibitor currently used in the treatment of diabetes. Using 2-
butyn-1,4-diol as the dipolarophile reagent and 2-azidoethanol, as a model, and then
azido-deoxyglycosides in a copper-catalyzed azide-alkyne cycloaddition (CuAAC),
a series of 1,4,5-trisubstituted 1,2,3-triazole derivatives were obtained in high yield
(Fig. 13.4) [45]. As a result, 6-deoxyglucosyl triazole
78
displayed good compet-
itive inhibition toward
-glucosidase (Ki 73 mM), being fourfold more potent as
compared to unglycosylated triazole
79
and twice more active than acarbose for this
particular enzyme. Nevertheless, the tests performed with a panel of glycosidases
revealed that pseudooligosaccharides
80
,
81
,
82
and
83
, comprising the trisaccha-
ride core present in acarbose, were not active. Therefore, these results suggested
that the bis(hydroxymethyl)triazole unit is not a functional surrogate of the natural
aminocyclitol moiety (valienamine) present in acarbose [45].
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