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O
HN
HO
OH
O
HO
O
O
HO
i.Cu wire/propanol
N
OH
O
N
N
O
N
ii.40% MeNH
2
/H
2
O
O
N
3
9
+
H
N
11
HO
H
8
Cu wire/propanol
HO
OH
O
O
N
10
N
N
N
HO
H
12
SCHEME 13.2
Synthesis of galactosyl oximes
11
and
12
with subsite B-binding 1,2,3-
triazoles at C3.
Cu(I)-catalyzed reactions, as potential galectin inhibitors [20]. Initially, a series of tri-
azoles was obtained at the C3 position of galactose by CuAAC reaction (CuI/DIPEA
in toluene, rt-40
◦
C) of 3-azide-GalSMe
13
with different monosubstituted-aryl
alkynes, as exemplified for triazole
14
(Scheme 13.3). Subsequently, considering
that LacNAc are far superior to galactose as natural ligands for galectins, several
LacNAc derivatives carrying 4-carbamoyl and 4-aryl triazoles at the galactose C3
were obtained by click reactions of LacNAc C3
-azido
15
and corresponding alkynes,
as shown for compound
16
(Scheme 13.3). Lastly, a panel of thiodigalactoside triazole
amides was synthesized in steps, starting with the preparation of the thiodigalactoside
triazole ester
17
by cycloaddition reaction between the galacto-azide
18
and methyl
propiolate
9
. The formed triazole was then treated with HBr and to the resulting
bromide
19
was added dried sodium sulfide, which led to its dimerization. As the last
step, reactions of
17
with a series of primary amines in methanol afforded the respec-
tive amides, as illustrated for the thiodigalactoside triazole butyl-amide
20
(Scheme
13.3). In general, the obtained compounds proved to be better inhibitors of galectin-3
if compared to other galectins subtypes (7, 8N and 9N), in competitive Fluorescence
polarization assays. The highest inhibitory activities toward galectin-3 were verified
for compounds
16
(Kd 0.66
M) and
20
(Kd 0.029
M), related to LacNAc- and
thiodigalactoside-triazoles series, respectively [20].
Since lectin-carbohydrate interactions are generally weak, special efforts are often
required to achieve tighter binding of carbohydrate-based ligands to lectins. One of
the established strategies to improve such interactions is based on the concept of
the “glycoside cluster effect,” which is related to the number and the geometry of
carbohydrate residues and also depends on their steric bulk, density, and relative
distance, as well as on their three-dimensional arrangement [21]. According to this
concept, the affinity enhancements observed for multimeric ligands over monomeric
species is often greater than predicted from the sum of the constitutive interac-
tions. Within this context, multimeric lactosides based on carbohydrate scaffolds
with valences ranging from 1 to 4 and different linker lengths were synthesized by
CuAAC reactions as inhibitors of galectins-1 and -3 (Scheme 13.4) [22]. To achieve
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