Conformationally restricted glycoside derivatives as mechanistic probes and/or inhibitors of sugar processing enzymes and receptors - Carbohydrate Chemistry: Chemical and Biological Approaches - page 426

HO HO

HO N

HO

HO N

HO

N
HO

HO HO HO HO

HO HO HO HO

NH

OH

HO

35 36 37 38

Fig. 12 Structures of calystegine 35, castanospermine 36, DNJ 37 and NJ 38.

OMe

O

OH

O

S O O

O NBu

O N

OH

HO

HO

N
HO

N
HO

HO HO

N
HO OH

N
HO

HO HO

HO

HO

HO

OH

OH

OH

40

39

42

41

4

S N O O

N O O

S

O O

N
HO

N N

HO

HO HO HO

HO HO OH

HO

HO

OH S

dansyl

O
HO OMe

44 45

O

43

n

HO

Fig. 13 Structures of castanospermine analogs 39-45.

nitrogen with increased sp 2 character, they reasoned that the resulting
iminosugar derivatives would exhibit higher stability as well as con-
figurational integrity in aqueous solution owing to the enhanced
anomeric effect. Amongst many compounds synthesized, the thiocarba-
mate 39 and carbamate 40 were selective yeast a-glucosidase inhibitors 60
as well as the isourea-type glycomimetic 41. 61 Later on, bicyclic isourea
derivatives with a D -galacto configuration such as 42 were reported by
Aguilar-Moncayo et al. 62 displaying significant nanomolar b-glucosidase
inhibition. Fluorescently-labelled iminosugar inhibitors were also pro-
duced 63 incorporating dansyl 43, dapoxyl or coumarin fluorophores at
the exocyclic nitrogen atom and allowing real-time and continuous
monitoring of b-glucosidase inhibition via fluorescence resonance energy
transfer (FRET) experiments. 64 In parallel, N-, S- and C-glycosyl analogues
of castanospermine such as 44 displaying aliphatic chains at the a-
configured pseudoanomeric position were synthesized, 65 demonstrating
high selectivity and anity for yeast neutral a-glucosidase II (K i 0.54-
3.4 mM) and antiproliferative activities on the growth of human breast
carcinoma cell lines (MCF-7). More recently, S´nchez Fern´ndez et al. 66
devised a synthetic route to the O-, S- and N-glycosyl derivatives as con-
formational mimics of a-linked disaccharides, the isomaltose mimic 45
exhibiting potent and selective inhibitory activities against isomaltase
and maltase (Fig. 13).
Guanidinium and isothiourea derivatives such as 46 and 47 were also
reported that exhibited potent and selective b-glycosidase inhibitory
activity, in contradiction with the previous castanospermine analogues
depicted above. 67 Noteworthy, sulfamide-type indolizidines such as 48,in
which the thiourea moiety has been replaced by a sulfamide group,
were also described and found to be modest a-mannosidase inhibitors