Synthesis and evaluation of sulfamide-type indolizidines as glycosidase inhibitors

Bioorg Med Chem Lett. 2008 May 1;18(9):2805-8. doi: 10.1016/j.bmcl.2008.04.004. Epub 2008 Apr 4.

Abstract

A practical synthesis of reducing sulfamide-derived iminosugar glycomimetics related to the indolizidine glycosidase inhibitor family is reported. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a synthetic scheme that involves 5,6-cyclic sulfamides. Further intramolecular nucleophilic addition of the sulfamide nitrogen atom to the masked aldehyde group of the monosaccharide in the open chain form afforded the target sugar mimics. By starting from d-glucose and d-mannose precursors, 2-aza-3,3-dioxo-3-thiaindolizidine derivatives with hydroxylation profiles that matched those of (+)-castanospermine and 6-epi-(+)-castanospermine were obtained. In vitro screening against a panel of glycosidases evidenced a high selectivity towards alpha-mannosidase.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry
  • Cell Line / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Glycoside Hydrolases / antagonists & inhibitors*
  • Humans
  • Hydroxylation
  • Indolizidines / chemical synthesis
  • Indolizidines / pharmacology*
  • Indolizines / chemistry
  • Indolizines / pharmacology
  • Models, Chemical
  • Molecular Mimicry
  • Stereoisomerism
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology*
  • alpha-Mannosidase / antagonists & inhibitors

Substances

  • Aldehydes
  • Enzyme Inhibitors
  • Indolizidines
  • Indolizines
  • Sulfonamides
  • Glycoside Hydrolases
  • alpha-Mannosidase
  • castanospermine