Synthesis of and a comparative study on the inhibition of muscle and liver glycogen 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-deoxy-beta-D-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as the major products. On the other hand, thiocyanate ions gave spiro-thiohydantoins with an inverted anomeric carbon as the only products. On the basis of radical inhibition studies, a mechanistic rationale was proposed to explain this unique stereoselectivity and the formation of C-(1-hydroxy-beta-D-glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms of muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and spiro-thiohydantoin 14 to be the best and equipotent inhibitors with K(i) values in the low micromolar range. The study of epimeric pairs of D-gluco and D-xylo configurated spiro-hydantoins and N-(D-glucopyranosyl)amides corroborated the role of specific hydrogen bridges in binding the inhibitors to the enzyme.
Somsák
L
L
Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary. somsak@tigris.klte.hu
Kovács
L
L
Tóth
M
M
Osz
E
E
Szilágyi
L
L
Györgydeák
Z
Z
Dinya
Z
Z
Docsa
T
T
Tóth
B
B
Gergely
P
P
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry; D008099:Liver / Q000201:enzymology*; D008968:Molecular Conformation; D009005:Monosaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D009132:Muscles / Q000201:enzymology*; D010762:Phosphorylase a / Q000037:antagonists & inhibitors; D010763:Phosphorylase b / Q000037:antagonists & inhibitors; D006005:Phosphorylases / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D006827:Hydantoins; D007004:Hypoglycemic Agents; D009005:Monosaccharides; D013141:Spiro Compounds; D010762:Phosphorylase a; D010763:Phosphorylase b; D006005:Phosphorylases