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HOOC
N
HO
OH
N
N
3
N
O
SPh
O
AcO
COO
t
-Bu
OAc
HO
O
5
SPh
i. CuI/ DIPEA
THF
3
O
+
AcO
ii. NaOMe
1
N
N
3
Ph
HO
OH
N
N
O
SPh
O
HO
6
4
AcO
OAc
N
3
O
i. CuI/ DIPEA
THF
HO
OH
AcO
+
O
COO
t
-Bu
AcO
HO
ii. NaOMe
N
HO
3
2
N
COOH
N
7
SCHEME 13.1
Synthesis of triazoles
5
-
7
by click reaction.
bonds, and their high polarity, synthesis of anomeric and O-3 triazole analogs of
galactosides has been developed to obtain higher affinity inhibitors of galectins 1- and
-3. Thus, click 1,3-dipolar cycloaddition reactions between galactosyl alkynes
1
and
2
with azides
3
or
4
, using CuI/DIPEA as catalytic system in THF, provided the triazole-
galactosyl derivatives
5
-
7
(Scheme 13.1) [18]. The best inhibitory activities in the
qualitative hemagglutination inhibition assays were verified for compounds
1
and
5
,
which showed to be 40 times more active than galactose at 1.25 mM concentration.
The CRD of galectins is composed by four subsites (A-D) which, along their 135
aa, form a groove able to bind up to a tetrasaccharide. Galactose binds to the most
conserved subsite C whereas the second more important subsite D is occupied by
another pyranoside represented by (1
→
→
3) GlcNAc/GalNAc
linked to galactose (subsite C) [19]. Therefore, the affinity enhancement for the
different subsites of galectins by combining structural fragments to galactoside or
lactoside derivatives may represent a significant approach. In this perspective, two
galactosyl oximes having C3-triazole fragments were prepared by CuAAC reac-
tions between the 3-azido-Gal-indol-carbaldoxime
8
and the corresponding alkynes
methyl propiolate
9
and phenyl acetylene
10
, in the presence of Cu wire in propanol
(Scheme 13.2). The obtained compounds
11
and
12
showed promising affinities for
galectin-3, with Kd values of 11
4)Glc/GlcNAc or (1
M, respectively, in Fluorescence polar-
ization assays. The improved affinity and selectivity of
11
and
12
for galectin-3 was
further justified through their modeling into the binding sites of different galectins.
It was then observed that, apart from interacting with subsites B and C present in all
galectins, these compounds were able to establish an extra strong interaction, through
their indole aldoxime fragments, with the Arg144 residue present in a distinct cavity
existent only in galectin-3 [19].
Following the strategy of getting ligands able to interact with the different subsites
(A-D) of galectins, a set of 3-triazol-galactosides, 3
-triazol-N-acetyllactosamine
(LacNAc), and di-triazol-thiodigalactoside derivatives were synthesized, under
M and 17
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