Alpha-1-C-alkyl-1-deoxynojirimycin derivatives as potent and selective inhibitors of intestinal isomaltase: remarkable effect of the alkyl chain length on glycosidase inhibitory profile

Bioorg Med Chem Lett. 2004 Dec 20;14(24):5991-5. doi: 10.1016/j.bmcl.2004.09.086.

Abstract

A series of alpha- and beta-1-C-alkyl-1-deoxynojirimycin derivatives was prepared and evaluated as glycosidase inhibitors. Biological assays showed a marked dependence of the selectivity and potency of the inhibitors upon the position of the alkyl chain (alpha-1-C-, beta-1-C- or N-alkyl derivatives). In addition, the efficiency of alpha-1-C-alkyl-1-deoxynojirimycin derivatives as intestinal isomaltase inhibitors increases with the length of the alkyl chain. The strongest inhibition was found for alpha-1-C -nonyl-1-deoxynojirimycin with an IC50=3.5 nM (25x more potent inhibitor than the shorter chain homologue carrying a C8 chain). These results demonstrate that subtle changes in the aglycon fragment may result in remarkable enzyme specificity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / chemical synthesis
  • 1-Deoxynojirimycin / pharmacology*
  • Animals
  • Evaluation Studies as Topic
  • Glycoside Hydrolases / antagonists & inhibitors*
  • Intestine, Small / enzymology*
  • Molecular Structure
  • Oligo-1,6-Glucosidase / antagonists & inhibitors*
  • Rats
  • Structure-Activity Relationship

Substances

  • 1-Deoxynojirimycin
  • Glycoside Hydrolases
  • Oligo-1,6-Glucosidase