Iminosugars/Azasugars - Glycosidase Inhibitors

  • Lundt, Inge (Project Manager)
  • Godskesen, Michael Anders (Project Participant)
  • Malle, Birgitte Mølholm (Project Participant)
  • Tagmose, Tina Møller (Project Participant)
  • Andersen, Søren Møller (Project Participant)
  • Wagner, Sussi Holstein (Project Participant)
  • Stütz, Arnold E. (Project Participant)

Project Details

Description

Glycosidases and glycosyltransferases are instrumental in the processing of various glycosylated proteins, which are ubiquitous in nearly all forms of life and play an important role in molecular recognition, adhesion and transport. The profound impact of these enzymes on life processes has made them desirable targets for inhibition. Glycoprocessing inhibitors have been used to treat diabetes, and have a potential as antiviral and antitumor agents.
Important groups of inhibitors are azasugars and carbasugars, compounds which have structure similar to sugars, but in which the ring oxygen has been replaced by a nitrogen or a methylene group, respectively. These compounds mimic the sugar in question by occupying the catalytically active site in the enzyme, thus preventing the hydrolysis/glycosylation.
Recently we found that azasugars having the anomeric carbon replaced by a nitrogen were very potent beta-glycosidase inhibitors.
Our approach to synthesize azasugars is stereocontrolled reactions starting from the chiral pool, namely the easily available sugar lactones. We have developed one step procedures for regioselective functionalizations of aldonolactones from which azasugars can be prepared in two to four steps. This appears to be the most general non-enzymatic synthetic procedure of potentially glycosidase inhibitors from carbohydrate precursors without the use of any protecting groups. - The investigations will focus on synthesis of aza/iminosugars having nitrogen in place of the ring oxygen, as well as nitrogen replacing the anomeric carbon, having other hydroxy groups modified as well in search for good glycosidase inhibitors/transition state analogues. More specific studies towards synthesis of inhibitors for a polysaccharide degrading enzyme is in progres.
StatusActive
Effective start/end date01/01/199501/01/9999