IMINOSUGAR C-GLYCOSIDES AS POTENTIAL THERAPEUTIC AGENTS: SYNTHESIS AND BIOLOGICAL EVALUATION

Olivier R. Martin

Institut de Chimie Organique et Analytique, CNRS & Université d’Orléans,

Rue de Chartres, BP 6759, 45067 Orléans, France

Sugar analogs carrying nitrogen at the position of the endocyclic oxygen atom, known as iminosugars, form one of the most interesting class of glycomimetics [1]. The scope of the biological activities of iminosugars, initially known as potent glycosidase inhibitors, has considerably widened in recent years, as they have been found to be inhibitors of glycosyl transferases, glycogen phosphorylase, nucleoside-processing enzymes, metalloproteinases, etc. [2].  Furthermore, derivatives of iminosugars, especially N-alkylated piperidinols, were shown, for example,  to exhibit potent antiviral activities and to have a protective effect in patients with Gaucher disease, an inherited lysosomal disorder. These compounds are therefore of growing interest as new therapeutic leads and two simple iminosugar derivatives have already been approved as drugs: Glyset^TM for the treatment of complications associated with type II diabetes, and Zavesca^TM (N-butyl-1-deoxynojirimycin)  for the treatment of Gaucher disease. 

While most iminosugar derivatives are, in fact, iminoalditols (no ‘aglycone’ substituent at the anomeric carbon), we have shown that the addition of a C-1 substituent, to generate pseudo-iminoglycosides, could greatly increase the selectivity of iminosugars toward families of glycosidases: such selectivity is a requirement for iminosugars to become therapeutic agents. We intend to present in this seminar an overview of synthetic strategies leading to such imino-C-glycosides with complete control of the configuration of the pseudo-anomeric center, and providing access to a wide diversity of aglycone structures.  Results of biological investigations on novel derivatives such as a-linked pseudoglycosides 1-3, including their evaluation as inhibitors of human b-glucocerebrosidase,  will be presented.

[1]           Stütz, A.E., Ed. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond  Wiley-VCH: New York, 1999.

[2]           Compain, P.; Martin, O.R., Eds.  Iminosugars: Recent Insights into their Bioactivity and Potential as Therapeutic Agents, Curr. Top. Med. Chem.  2003, 3, issue 5.