Nitrogen-in-the-ring pyranoses and furanoses: structural basis of inhibition of mammalian glycosidases

J Med Chem. 1994 Oct 28;37(22):3701-6. doi: 10.1021/jm00048a006.

Abstract

Seven pyranoses and three furanoses with a nitrogen in the ring were prepared by chemical synthesis, microbial conversion, and isolation from plants to investigate the contribution of epimerization, deoxygenation, and conformation to the potency of inhibition and specificity of mammalian glycosidases. The seven pyranoses are 1-deoxynojirimycin (1), the D-manno (2), D-allo (3), and D-galacto (4) isomers of 1, fagomine (1,2-dideoxynojirimycin, 5), and the D-allo (6) and D-galacto (7) isomers of 5, while the three furanoses are 2,5-dideoxy-2,5-imino-D-mannitol (8), 1,4-dideoxy-1,4-imino-D-arabinitol (9), and 1,4-dideoxy-1,4-imino-D-ribitol (10). The 2-deoxygenation and/or 3-epimerization of 1 enhanced the potency for rat intestinal lactase and bovine liver cytosolic beta-galactosidase. Especially compound 6 showed a potent inhibitory activity against both enzymes, and compound 8, a mimic of beta-D-fructofuranose, was a potent inhibitor of both beta-galactosidases as well. Compound 4, which has been known as a powerful alpha-galactosidase inhibitor, exhibited no significant inhibitory activity for most of mammalian beta-galactosidases. In addition, compound 6 fairly retained a potency of 1 toward rat intestinal isomaltase. In this study, compound 8, known as a processing alpha-glucosidase I inhibitor in cell culture, has been found to have no effect on processing alpha-glucosidase II, whereas 9 has been shown to be a good nonspecific inhibitor of intestinal isomaltase, processing alpha-glucosidase II, Golgi alpha-mannosidases I and II, and porcine kidney trehalase. It has been speculated that glycosidase inhibitors have structures which resemble those of the respective glycosyl cations. This Broad inhibitory activity of 9 toward various glycosidases suggest that it superimposes well on the various glycosyl cations.

MeSH terms

  • Animals
  • Carbohydrates / chemistry*
  • Carbohydrates / pharmacology
  • Cattle
  • Epididymis / enzymology
  • Furans / chemistry
  • Furans / pharmacology
  • Glycoside Hydrolase Inhibitors
  • Glycoside Hydrolases / antagonists & inhibitors*
  • In Vitro Techniques
  • Intestinal Mucosa / enzymology
  • Kinetics
  • Liver / enzymology
  • Male
  • Mannosidases / antagonists & inhibitors
  • Nitrogen / chemistry*
  • Pyrones / chemistry
  • Pyrones / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Trehalase / antagonists & inhibitors
  • beta-Galactosidase / antagonists & inhibitors

Substances

  • Carbohydrates
  • Furans
  • Glycoside Hydrolase Inhibitors
  • Pyrones
  • Glycoside Hydrolases
  • Mannosidases
  • beta-Galactosidase
  • Trehalase
  • Nitrogen