Conformationally restricted glycoside derivatives as mechanistic probes and/or inhibitors of sugar processing enzymes and receptors - Carbohydrate Chemistry: Chemical and Biological Approaches - page 422

OH

HO

HO

CO 2 H

N N N

RO

HO

N

N N

HO HO HO

OH OH

NHAc

11 12 13 R = xylopyranose

HO

N

HO

N

HO

NH

O

14

Fig. 5 Structures of glycoimidazoles 11-14.

1,4 B CONFORMATION. The Antiperiplanar Lone Pair Hypothesis
(ALPH) proposes that hydrolysis of b- D -glycopyranosides involves a con-
formational change of the sugar ring from a chair to a 1,4 B boat or twist-
boat conformer as heterolytic cleavage of an acetal C-O bond requires an
antiperiplanar orientation of a doubly occupied, non-bonding orbital to
meet the principle of stereoelectronic control. 30 Therefore inhibitors
displaying a positive charge properly located and adopting such con-
formation may be closer transition state mimics of an oxycarbenium
type. Of note 1,4 B conformation has been observed for the sugar residue
bound at subsite 1 of chitinase A. 31

Polyhydroxylated isoquinuclidines. With the aim to extend the ALPH to
enzymic glycoside hydrolysis, Vasella and co-workers reported in 2000 the
synthesis of polyhydroxylated isoquinuclidines derivatives mimicking the
1,4 B boat conformation of a mannopyranoside. 32 The N-benzyl D -manno-
configured bicycle 15 proved to be a highly potent competitive and
selective snail b-mannosidase inhibitor (K i 0.17 mM) whilst being com-
paratively a poor ligand of jack bean a-mannosidase (IC 50 9.6 mM) and
b-glucosidase (IC 50 W5 mM). In this context, homoisoquinuclidine 16 was
synthesized as it possesses a longer bridge ensuring almost a 1,4 Bcon-
formation. 33 Compound 16 was a poor inhibitor of mannosidases in sharp
contrast to the related isoquinuclidine 15. This can be tentatively attrib-
uted to steric interactions imposed by the larger ethylamino bridge. This
type of scaffold was further exploited to lead to the D -gluco-configured
derivatives such as 17 32b that displayed only weak inhibition towards
b-glucosidases from C. saccharolyticum, sweet almonds and cellulase Cel7A
from Trichoderma reesei and b- D -glucan glucohydrolase evidencing a
different conformational itinerary for these families of glycosidases. As
several crystal structures of hexosaminidases belonging to families GH18
and GH20 suggested a similar conformational change during glycosidic
bond cleavage, 34 several 1,4 B locked acetamido-isoquinuclidine derivatives
including 18 35 were synthesized. Compound 18 proved to be a competitive
nanomolar inhibitor of jack bean N-acetyl-b-hexosaminidase (K i 14 nM)
and bovine kidney N-acetyl-b-hexosaminidase (K i 67 nM) (Fig. 6).

Polyhydroxylated norbornanes and derivatives. To more closely mimic
the 1,4 B conformation, the norbornane derivative 19 and the oxygenated