CLICK CHEMISTRY APPLIED TO CARBOHYDRATE-BASED DRUG DISCOVERY - Click Chemistry in Glycoscience: New Developments and Strategies - page 337

OAc OAc

O

O

Ac AcO

AcO
AcO

N 3

OAc

AcO

N 3

β -D-Glc p -azide 84 α− D-Glcp-azide 85

N N

N N

O

N

N N

R

N

OH

N

R

R

86a R = β -D-Glc p 87a R = -D-Glc p 88a R = β -D-Glc p

β

86b R = α -D-Glc p 87b R = α -D-Glc p 88b R = α -D-Glc p

N N

N N N N N N

N

OH

O NH 2 N

O

N N N

R

R R

R

O

O O

89a R = β -D-Glc p 90a R = β -D-Glc p

90b R = α -D-Glc p

91a R = β -D-Glc p
91b R =

92a R = β -D-Glc p
92b R = 89b R = α -D-Glc p -D-Glc p -D-Glc p

α α

O

N N

N N

N N

N N

OH

β -D-Glc p N

N

β -D-Glc p N

OH

β -D-Glc p N -D-Glc p N β

O

93

94 95 96

N N N N N N

OH OH

O

OH

β -D-Glc p N β -D-Glc p N β -D-Glc p N

97 98 99

FIGURE 13.5 Structures of glucopyranosyl triazoles 86a-92b , 93-99 , as potential glycosi-

dase inhibitors.

effect in the inhibitory potency of most glycosidases and the goal to enhance affinity
of multivalent iminosugars has not been achieved, despite the selectivity and activity
obtained for

-mannosidase, and amyloglucosidase (Table 13.2) [48].
The search for hybrid inhibitors able to target two different enzymes of the angio-
genesis pathway has been pursued by combining 1-deoxynojirimycin (DNJ) and 5-
aryl-1,2,3-triazole in a single hybrid molecule connected by different linkers length
(Fig. 13.7) [49]. In this regard, DNJ core was used as

-glucosidase,

-glucosidase inhibitor to
disturb the oligosaccharide biosynthesis on endothelial cell surface and 5-aryl-1,2,3-
triazole unit as potential methionine aminopeptidase II (MetAP2) inhibitor, whose
activity is assessed by BAEC proliferation [49].
The resulting bifunctional derivatives were evaluated for their

-glucosidase (from
Bacillus stearothermophilus ) inhibitory activity, being compound 107 (IC 50 1.15 M)

more potent than DNJ (IC 50 1.67 M), and compounds 105 (IC 50 6.07 M) and 106

(IC 50 2.41 M) being more efficient to alter the biosynthesis of oligosaccharides on

endothelial cell surfaces when compared with DNJ. Therefore, the seven methylene
linker that holds the two active units in compound 107 may contribute for favorable
interactions in the active site, since the precursor aryl-1,2,3-triazole did not exhibit