Conformationally restricted glycoside derivatives as mechanistic probes and/or inhibitors of sugar processing enzymes and receptors - Carbohydrate Chemistry: Chemical and Biological Approaches - page 423

OH OH OH

OH

BnN OH HN HN OH BnN OH

HO
HO

HO HO

HO
HO

15 16 17 18

NHAc

HO

Fig. 6 Structures of isoquinuclidines 15-18.

N

OH

X O

HO HO

COOH

HO

NH 2

HO
H 2 N
19

HO

HO NH 2
21

22

X = CH 2
20 X = O

Fig. 7 Structures of norbornane derivatives 19-22.

HO

N

OH

HO

OH

HO

H HO

H HO

NH

OH

NH 2

23 24 25

Fig. 8 Structures of isofagomine 23, aziridine 24 and cyclopropylamine 25.

analogue 20 displaying a shorter bridge between the sugar-like C1 and C4
carbon atoms were reported and required, unlike isoquinuclidines, exo-
cyclic location of the amine. 36 Unfortunately these derivatives, that can
be seen as early TS mimics, proved to be only weak inhibitors of b-glu-
cosidases and b-mannosidases. Of note is the b-galacturonidase inhibitor
21 based on a dioxabicyclo[2.2.1]heptane scaffold developed by Koert. 37
In a similar approach, Vogel explored the potential of a 7-azabicy-
clo[2.2.1]heptane scaffold to generate a series of locked diamine inhibi-
tors including 22, some of them being moderate inhibitors of several
glycosidases (Fig. 7). 38

Aziridine and cycloprolylamine derivatives. According to stereoelectronic
effects, isofagomine 23, a highly potent b-glucosidase inhibitor developed
by Bols 39 that adopts a 4 C 1 chair conformation in solution, might bind
glycosidases in a distinct boat-like conformation. The peculiar slow onset
binding of 23 to b-glucosidase, consistent with an energetically unfavour-
able and little populated conformation binding to the enzyme, also sup-
ported this hypothesis. These assumptions led the authors to synthesize a
bicyclic aziridine analogue 24 40 that did not inhibit almonds b-glucosidase.
On the opposite, a similar derivative 25 incorporating a cyclopropylamine
moiety reported by Vasella 41 proved to be a good a-mannosidase inhibitor
(IC 50 80 mM) in keeping with the ALPH postulate (Fig. 8).

2,5 B CONFORMATION. Despite the fact that it places the CH 2 OH group
at C5 in an unfavourable pseudoaxial position, 2,5 B conformation has been
proposed for the transition state of a limited number of glycosidases. X-ray
crystallography has revealed that a cellobio-derived isofagomine, a