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In-Depth Information
OH
OH
HO
HO
OH
HO
O
N
N
O
N
N
N
N
N
N
N
HO
OH
HO
HO
HO
OH
OMe
O
O
HO
OH
78
79
80
HO
O
HO
OH
OH
OH
O
OH
HO
OH
HO
OH
O
HO
O
HO
HO
O
OH
HO
HO
HO
OH
OH
HO
HO
O
HO
O
HO
HO
O
OH
O
HO
HO
N
N
N
O
O
HO
OH
HO
82
HO
N
N
N
O
N
N
N
O
O
O
HO
OH
OH
HO
OH
HO
HO
HO
HO
O
O
O
O
O
HO
83
OH
HO
OH
HO
OH
HO
HO
OH
81
O
O
HO
HO
OH
OH
OH
OH
FIGURE 13.4
Structures of 1,2,3-triazolo-pseudooligosaccharides triazole mimetics
80-83
,
designed from acarbose.
-D-glucopyranosyl triazoles having variable
aglycones was synthesized, via CuAAC reactions, as potential glycosidase inhibitors
[39]. Hence, the coupling between
A small library of 21
-D- and
-D-glucopyranosyl azide
84
or the corresponding
isomer
85
with selected alkynes bearing a wide variety of functional groups, under
reaction conditions involving the use of the catalytic system CuSO
4
/sodium ascorbate,
afforded compounds
86a-92a
/
86b-92b
(Fig. 13.5). Alternatively, the application of
the catalytic system CuSO
4
/Cu turnings using
-D-glucopyranosyl azide
84
and
other alkynes, gave compounds
93-99
(Fig. 13.5) [46]. The impact of glycosyl
azide anomeric configuration on the rate of CuAAC reactions was investigated to
distinguish
-
glucopyranosyl azide were typically complete in 10-45 minutes, similar reaction
conditions performed with
- and
-glucopyranosyl azides reactivities. While reactions with
-glucopyranosyl azide often required 45-120 minutes.
This difference was further investigated using competition reactions and rationalized
on the basis of X-ray crystallographic data, which revealed significant differences in
bond lengths within the azido groups of
-anomers [47].
Iminosugars, such as DNJ, have great potency and specificity to inhibit glucosi-
dases due to their ability to mimic the transition state of natural glucosidase substrates
[42]. Based on the single binding center and on the conformational and electrostatic
influences of DNJ in a panel of glucosidases, the synthesis of multivalent iminosugars
was carried out with the aim to modulate affinity and selectivity for glycosidases [48].
Thus, mono-(
100
,
101
), di-(
102
,
103
), and trivalent derivatives
104
were obtained
by a click chemistry approach using the 1,3-dipolar cycloaddition between azide-
functionalized 1-DNJ derivatives and alkynyl-armed oligo(ethyleneglycol) (EG) scaf-
folds in the presence of CuSO
4
/sodium ascorbate in a mixture of dioxane and water
[48] (Fig. 13.6). CuAAC was highly regioselective and afforded only 1,4-disubstituted
triazole structures, which bear different number of active DNJ moieties and length
between the functional epitopes. The inhibition assays were performed against sev-
eral glycosidases using 1-DNJ for comparative purpose. In general, the incorporation
of EG spacers, containing the triazole unit at the nitrogen ring, had a deleterious
- and
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