Chemistry Reference
In-Depth Information
HO
HO
O
N
O
HO
HO
O
OH
HO
HO
N
N
NHAc
O
NHAc
6
7
Fig. 3 Structures of PUGNAc 6 and LOGNAc 7.
OH
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
HO
OPO
3
H
2
NH
2
NH
2
8
9
10
Fig. 4 Structure of valienamine 8 and cyclopropane derivatives 9-10.
Hex A.
19
It is interesting to note that the related N-acetylglucosaminono-
1,5-lactone oxime LOGNAc 7
20
that lacks the phenyl carbamate moiety is
a weaker inhibitor emphasizing the importance of the aromatic aglycon
(Fig. 3).
Valienamine derivatives. Another strategy to force the sugar ring to
adopt a half-chair conformation was developed by Bennet.
21
Cyclopro-
panation of the C
ΒΌ
C bond of natural product valienamine 8
22
produced a
very potent a-glucosidase inhibitor 9 (K
i
107 nM) based on a bicy-
clo[4.1.0]heptane carbocyclic framework. This compound was further
modified to yield an analogue of glucose-1-phosphate 10
23
that demon-
strated only weak inhibition on glucose 1-phosphate uridyltransferase,
the enzyme that converts glucose-1-phosphate into UDP-glucose (Fig. 4).
Glycoimidazoles. This family of inhibitors finds its origins in the nat-
ural product nagstatin 11,
24
a potent hexosaminidase inhibitor based on
a fused polyhydroxylated piperidine-imidazole motif displaying a
D
-Gal-
NAc configuration. Nagstatin 11 exhibits key features that are responsible
for its high potency. It adopts a
4
H
3
conformation due to the sp
2
character
of the anomeric center. The imidazole ring provides a non-bonding
doubly occupied nitrogen orbital for anti-protonation and is suciently
electronegative to permit a simultaneous interaction with the enzyme
catalytic nucleophile. Furthermore protonation of the imidazole ring
effectively emulates the charge distribution in the oxycarbenium ion. The
groups of Tatsuta and Vasella have developed complementary synthetic
routes to nagstatin analogues
25
including glycoimidazole 12 that have
been very useful to illustrate the notion of glycosidase-mediated lateral
protonation.
26
Many derivatives have been reported since including a
pseudoxylobioside 13.
27
Another striking example is GlcNAcstatin 14,a
synthetic picomolar and selective OGA inhibitor that modulates intra-
cellular O-GlcNAcylation levels (Fig. 5).
28
2.2 Conformationally restricted glycosidase inhibitors adopting boat
conformations
Boat conformations have emerged as increasingly important in the field
of glycosidases as they have been observed or proposed for the
pseudorotational itinerary of a growing number of enzymes.
29
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