Synthesis of thiodisaccharides as inhibitors of glycosidases. Oxidation of the interglycosidic sulfur atom to sulfoxides and sulfones

COLOMER, J. P.; MANZANO, V. E.; VARELA, O.

Simposio; XXVIth International Carbohydrate Symposium; 2012

International Carbohydrate Organization

Thiooligosaccharides constitute an important class of sulfur analogues of naturally occurring oligosaccharides that are useful tools in glycobiology. They are usually stable to glycosyl hydrolases, in comparison to their natural counterparts, and in many cases they act as inhibitors of these enzymes. We have reported efficient strategies for the construction of the thioglycosidic linkage of thiooligosaccharides,1,2 and as part of our continuing interest in this subject, we describe here the synthesis and evaluation of the inhibitory activity of (1-3) and (1-4) thiodisaccharides with terminal glucose or galactose residues. The subsequent oxidation of the sulfur atom of these molecules afforded the respective sulfoxides and sulfones. A number of thiodisaccharides have been prepared by ring-opening reaction of oxirane derivatives of sugars, like 1. Thus, nucleophilic attack of 1-thioglucose or 1-thiogalactose (2) to the epoxide 1 afforded, after acetylation, thiodisaccharides of the kind of 3 or 4. A similar ring-opening of the 3,4-epithio derivative prepared from 1, gave regioselectively the (1-4) thiodisaccharides having the 3,4-dithio-a-D-gluco configuration for the reducing end. The oxidation of the sulfur atom of the thiodisaccharides was conducted with mCPBA. Thus, oxidation of 3 or 4 for short times (~3 h) afforded the diastereoisomeric mixture of sulfoxides 7 and 8 in 85% overall yield. Longer oxidation times led to the corresponding sulfones (9 and 10, 90% yield). In some cases, depending on the staring material, the diastereoisomeric sulfoxides could be separated by column chromatography. The acetylated thiodisaccharides and sulfoxides were treated with MeOH/Et3N/H2O to give the free compounds (i.e., 5, 6, 11 and 12). The analogous reaction applied to sulfones 9 and 10 led to unsaturated products by elimination of the acetyl groups vicinal to the sulfone. The free thiodisaccharides (such as 5 and 6) were evaluated as inhibitors against the b-galactosidase of E. coli. Sulfoxides of the kind of 11 and 12 are expected to act as antitumor agents.