Conformationally restricted glycoside derivatives as mechanistic probes and/or inhibitors of sugar processing enzymes and receptors - Carbohydrate Chemistry: Chemical and Biological Approaches - page 425

H 2 N

O O N

HO O HO N H HO N H

O H OH OH

HO HO HO

OH OH OH

29 30 31

Fig. 10 Structures of mannonolactone 29, mannonolactame 30 and mannoamidine 31.

HO

HO OH HO

OH

HO

N O OMe

HO

HO H HO

N

N

HO

NH 2

32 33 34

Fig. 11 Structures of derivatives 32-34.

closely related conformation by X-ray crystallography. 50 This was indeed
the case for mannoimidazole 32 that was the most potent derivative.
Additionally compound 33 locked in a B 2,5 conformation by a three
carbon link 54 demonstrated some binding on a catalytically com-
promised mutant despite unfavourable steric clashes. More recently, an
isofagomine analogue 34 incorporating an amidine moiety has been
shown to display potent and selective a-mannosidase inhibition, in
marked contrast to the corresponding isofagomine 23 suggesting a B 2,5
conformation for 34 (Fig. 11). 55

2.3 Conformationally restricted glycosidase inhibitors adopting chair
conformations
The 4 C 1 and 1 C 4 conformations have been observed for a number of
glycosidases in complex with substrates or inhibitors. For instance, the
4 C 1 conformation has been described for the atomic resolution structures
of xylobiose-derived isofagomine and xylobiose-derived DNJ in complex
with the xylanase Xyn10 from Streptomyces lividans. 56 Additionally,
naturally occurring bicyclic iminosugars restrained in a chair conform-
ation have been isolated from various sources. This includes calystegines
such as 35 57 and castanospermine 36 58 (Fig. 12), both demonstrating high
potency toward glycosidases. Consequently, many calystegine and
castanospermine analogues have been reported and evaluated as glyco-
sidase inhibitors.

Castanospermine analogues. Despite the fact that its rigidified bicyclic
structure contributes to its higher enzyme specificity compared with the
monocyclic analogues DNJ 37 and nojirimycin (NJ) 38, 59 it can be argued
that castanospermine lacks a pseudoanomeric substituent with a defined
configuration and thus can simultaneously inhibit several a- and b-
glycosidases, which remains an important issue for pharmaceutical
applications (Fig. 12).
This prompted the group of Garc´a Fern´ndez to develop castano-
spermine analogues incorporating a pseudoanomeric axial hydroxyl
group. By replacing the amine sp 3 nitrogen atom by a pseudoamide type
(urea, thiourea, isothiourea, carbamate, thiocarbamate, guanidinium)