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N
N
OH
OH
Lac
N
N
N
HOOC
O
N
S
O
O
NH
OH
Lac
18
N
N
N
O
H
3
CO
2
C
CO
2
CH
3
N
O
HN
R
O
NH
HN
O
R
17
O
O
N
NN
N
Lac
N
N
OH
O
O
O
O
OH
OH
OH
O
OH
HO
O
O
OH
O
O
HO
N
N
O
HO
OH
HO
OH
N
OH
OH
Kd=3.2 M
-
1 for galectn
μ
20
19
FIGURE 12.7
Biologically active triazolyl glycoconjugates.
cycloaddition reaction to afford a panel of mono-, di- and trivalent lactoside deriva-
tives. Among all, the divalent cluster
19
with K
d
value as low as 3.2
M was identified
as a promising galectin-1 inhibitor (Fig. 12.7) having a relative potency of 30 per
lactose unit as compared to the natural disaccharide ligand lactose [46].
Ernst et al. utilized click chemistry in preparation of a library of selectin antagonists
based on sialyl Lewis
x
(sLe
x
) structure where Neu5Ac was replaced by (
S
)-isoserine.
The sLe
x
residing on physiological selectin ligands are responsible for inflammation,
a protective attempt of body against pathogens. A series of 7 different alkynes were
inserted over sLe
x
based triazole but only the unsubstituted triazole and the azido
compound (
20
) displayed slightly improved affinities for E-selectin, while substituted
compounds showed affinity similar to sLe
x
(Fig. 12.7) [47].
Sialyl Lewis
x
(sLe
x
) and sialyl Lewis
a
(sLe
a
), the tetrasaccharides usually attached
to
O
-glycans on the surface of cells, are crucial for the cell-cell recognition processes
such as fertilization, embryogenesis, lymphocyte trafficking, immune responses, and
cancer metastasis. The enzyme fucosyltransferase catalyzes the last step of glycosy-
lation of sLe
x
and sLe
a
by facilitating transfer of L-fucose moiety from guanosine
diphosphate
-L-fucose (GDP-fucose) to a specific hydroxyl group of sialyl
N
-acetyl-
lactosamine. Wong et al. using Cu(I)-catalyzed 1,3-dipolar cycloaddition prepared
a library of 85 GDP-triazoles by keeping GDP as common scaffold, and varying
hydrophobic group and linker chain attached to it. The compound (
21
) with an
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