Synthesis of and a comparative study on the inhibition of muscle and liverglycogen phosphorylases by epimeric pairs of D-gluco- and D-xylopyranosylidene-spiro-(thio)hydantoins and N-(D-glucopyranosyl) amides

D-Gluco- and D-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure. In the key step of the syntheses C-(1-bromo-1-de oxy-beta -D-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as t he major products. On the other hand, thiocyanate ions gave spiro-thiohydan toins with an inverted anomeric carbon as the only products. On the basis o f radical inhibition studies, a mechanistic rationale was proposed to expla in this unique stereoselectivity and the formation of C-(1-hydroxy-beta -D- glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms o f muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and sp iro-thiohydantoin 14 to be the best and equipotent inhibitors with K-i valu es in the low micromolar range. The study of epimeric pairs of D-gluco and D-Xylo configurated spiro-hydantoins and N-(D-glucopyranosyl)amides corrobo rated the role of specific hydrogen bridges in binding the inhibitors to th e enzyme.