Fluorous Iminoalditols: A New Family of Glycosidase Inhibitors and Pharmacological Chaperones |
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| Authors: | Georg Schitter Andreas J Steiner Gerit Pototschnig Elisabeth Scheucher Martin Thonhofer Chris A Tarling Prof Stephen G Withers Katrin Fantur Prof Eduard Paschke Prof Don J Mahuran Brigitte A Rigat Prof Michael B Tropak Carina Illaszewicz Prof Robert Saf Prof Arnold E Stütz Prof Tanja M Wrodnigg |
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| Affiliation: | 1. Glycogroup, Deparment of Organic Chemistry, Graz University of Technology, Stremayrgasse 16, 8010 Graz (Austria), Fax: (+43)?316‐873‐8740;2. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C., V6T 1Z1 (Canada);3. Department of Pediatrics, Medical University Graz, Auenbruggerplatz 30, 8010 Graz (Austria);4. Department of Laboratory Medicine and Pathobiology, Sick Kids Hospital, University of Toronto, 555 University Avenue, Ontario M5G 1X8 (Canada);5. Institute for Chemistry and Technology of Materials, Graz University of Technology, Stremayrgasse 16, 8010 Graz (Austria) |
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| Abstract: | A collection of new reversible glycosidase inhibitors of the iminoalditol type featuring N‐substituents containing perfluorinated regions has been prepared for evaluation of physicochemical, biochemical and diagnostic properties. The vast variety of feasible oligofluoro moieties allows for modular approaches to customised structures according to the intended applications, which are influenced by the fluorine content as well as the distance of the fluorous moiety from the ring nitrogen. The first examples, in particular in the D ‐galacto series, exhibited excellent inhibitory activities. A preliminary screen with two human cell lines showed that, at subinhibitory concentrations, they are powerful pharmacological chaperones enhancing the activities of the catalytically handicapped lysosomal D ‐galactosidase mutants associated with GM1 gangliosidosis and Morquio B disease. |
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| Keywords: | chaperones enzymes fluorine glycosidases inhibitors |
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