Fluorous iminoalditols: a new family of glycosidase inhibitors and pharmacological chaperones.
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.
Schitter
Georg
G
Glycogroup, Deparment of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria.
Steiner
Andreas J
AJ
Pototschnig
Gerit
G
Scheucher
Elisabeth
E
Thonhofer
Martin
M
Tarling
Chris A
CA
Withers
Stephen G
SG
Fantur
Katrin
K
Paschke
Eduard
E
Mahuran
Don J
DJ
Rigat
Brigitte A
BA
Tropak
Michael B
MB
Illaszewicz
Carina
C
Saf
Robert
R
Stütz
Arnold E
AE
Wrodnigg
Tanja M
TM
D002460:Cell Line; D003069:Coffee / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004926:Escherichia coli / Q000201:enzymology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005696:Galactosidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016537:Gangliosidosis, GM1 / Q000188:drug therapy*; D054879:Halogenation; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D012231:Rhizobium / Q000201:enzymology; D013402:Sugar Alcohols / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D003069:Coffee; D004791:Enzyme Inhibitors; D007097:Imines; D013402:Sugar Alcohols; D005696:Galactosidases