Chemistry Reference
In-Depth Information
mannoside 57 and its 1,2,3-triazole derivatives were effective substrates, since the
partition of the reaction mixture between water and butan-1-ol, and analysis by
HPTLC detected by fluorography, showed the presence of disaccharides and higher
oligomers connected by
-1,2-linkage. In contrast, no substrate activity was observed
for methyl 6-azido-
-mannopyranoside 56 nor for any of its 1,2,3-triazole derivatives
when tested against
-1,2-mannosyltransferases from
L. Mexicana
[41].
13.4.3 Glucosidases
Glucosidases are involved in several biochemical processes such as degradation
of diet polysaccharides to furnish monosaccharide units, which are then able to
be metabolically absorbed and used by the organism, lysosomal glycoconjugate
catabolism and glycoprotein processing, and biosynthesis of oligosaccharide units in
glycoproteins or glycolipids. Glucosidase inhibitors are currently of interest owing
to their promising therapeutic potential in the treatment of disorders such as diabetes,
human immunodeficiency virus (HIV) infection, metastatic cancer and lysosomal
storage diseases. In this regard, many attempts have been made to utilize click
chemistry for the synthesis of potential glucosidase inhibitors [42].
The search for favorable binding interactions by mimicking glycosyl amines func-
tionalities, which can be protonated to interact with the carboxylate moieties on glu-
cosidase active site, led to the synthesis of glucosyl triazoles via a copper-catalyzed
[3
-azido glycosides
and phenylacetylene (Scheme 13.13) [43]. The biological assays carried out against
three
+
2] cycloaddition between the appropriate acetyl-protected
-glycosidases, sweet almond glucosidase (SAG),
Escherichia coli
galactosi-
dase (ECG), and bovine liver galactosidase (BLG) showed that only weak inhibition
was observed for compounds
58
(30%) and
59
(48%) against ECG and BLG glycosi-
dases, respectively, when tested 0.24 mM (Table 13.1) [43].
Glucosylceramide synthase (GCS) is an essential glucosyltransferase involved
in the biosynthesis of glucosylceramide, which is subsequently hydrolyzed into
ceramide and glucose by the action of the
-GCase). Defects
in the lysosomal degradation of glycosphingolipids due to the deficient activity of
-glucocerebrosidase (
-GCase led to glucosylceramide accumulation in macrophages and the development
of the Gaucher disease.
The iminosugar
N
-butyl-1-deoxynojirimycin (
N
-Bu-DNJ) is a potent inhibitor of
GCS, which reduces the glucosylceramide biosynthesis and minimizes the deficient
OAc
OAc
OH
R
1
R
1
R
1
HO
N
N
(iPr)
2
NEt
N
NaOMe
MeOH
N
R
2
R
2
R
2
O
O
O
Ph
Ph
N
N
N
3
AcO
AcO
copper(I) iodide
OAc
OAc
OH
Ph
H
60
R
1
= OAc, R
2
= H
61
R
1
= H, R
2
= OAc
62
R
1
= OAc, R
2
= H, (74%)
63
R
1
= H, R
2
= OAc, (75%)
58
R
1
= OH, R
2
= H
59
R
1
= H, R
2
= OH
SCHEME 13.13
Synthesis of glycosyl triazoles
58
and
59
, via copper-catalysed 3
+
2
cycloaddition, as glucosidase inhibitors.
Search WWH ::
Custom Search