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(a)
HO
HO
OH
HO
O
O
UGM
HO
HO
HO
O
UDP
O
OH
UDP
80
81
(b)
HO
HO
O
O
O
O
P
O
HO
HO
HO
UMP
P
UMP
OH
OH
OH
OH
83
82
1,4
B Boat
Fig. 23 a) Interconversion between UDP-Galp 80 and UDP-Galf 81 b) Structures of the
two C-glycosidic UDP-galactose derivatives 82 and 83.
state. Importantly, when this flavoenzyme was in its kinetically com-
petent state, the anity of the boat-locked molecule 82 was significantly
higher than its furanosidic 83 counterpart. These results strongly sug-
gested that the transient conformations of the galactose moiety during
the interconversion are close to a
1,4
B boat.
107
3.4 Conformationally constrained heparin fragments
Heparin, a sulfated polysaccharide belonging to the family of glycosa-
minoglycans, has been widely studied because of its numerous important
biological activities, such as anticoagulant and antithrombic activities.
108
A major breakthrough in heparinology was the identification of the
pentasaccharide sequence into heparin chain specifically interacting
with antithrombin (AT), the physiological inhibitor of activated blood
coagulation factors, and giving heparin its activity.
109
An analogue of the
pentasaccharide sequence 84 has been developped as a marketed
anticoagulant called Fondaparinux (Arixtra
s
) by Sanofi-Aventis then
GlaxoSmithKline. According to NMR studies of 84, the only
L
-iduronic
acid component could adopt an unusual
2
S
O
skew-boat conformation in
solution. This was also confirmed by calculations.
110
In order to investigate the relationship between this conformation
and the AT activity, Sina¨ and co-workers synthesized in 2001 three
pentasaccharides 85, 86 and 87 in which the
L
-iduronic acid residue is
conformationaly locked, either in
2
S
O
,
4
C
1
or
1
C
4
conformations, taking
pentasaccharide analogue 84 as reference (Fig. 24).
111
The results showed
that only the
2
S
O
-locked molecule was able to strongly activate AT with
respect to the factor Xa. The two pentasaccharides 86 and 87 presented
very slight inhibition against the blood coagulation protease factor Xa. In
conclusion, this study unambiguously demonstrated that the
L
-iduronic
acid unit G adopts the unusual
2
S
O
when it is bound to the AT and
explains the connection between the unique conformational behavior of
L
-iduronic acid and the biological activity.
3.5 Glucose cotransporter inhibitors
Diabetes is a chronic disease that occurs either when the pancreas does
not produce enough insulin (type 1) or in case of liver and peripheral
insulin resistance (type 2).
112
It affects 347 million people worldwide
113
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