N-Substituted 5-amino-1-hydroxymethyl-cyclopentanetriols: A new family of activity promotors for a GM1-gangliosidosis related human lysosomal β-galactosidase mutant.
From 1,2;3,4-di-O-isopropylidene-α-D-galactopyranose, a series of highly functionalized (hydroxymethyl)cyclopentanes was easily available. In line with reports by Reymond and Jäger on similar structures, these amine containing basic carbasugars are potent inhibitors of β-D-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for GM1-gangliosidosis-associated lysosomal acid β-galactosidase mutant R201C, thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease.
Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010, Graz, Austria.
Michael
M
Schalli
Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
Christina
C
Tysoe
Institute of Inorganic Chemistry Graz University of Technology, Stremayrgasse 9, A-8010, Graz, Austria.
Roland
R
Fischer
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036, Graz, Austria.
Bettina M
BM
Pabst
Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010, Graz, Austria.
Martin
M
Thonhofer
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036, Graz, Austria.
Eduard
E
Paschke
Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010, Graz, Austria.
Tanja
T
Rappitsch
Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010, Graz, Austria. Electronic address: stuetz@tugraz.at.
Arnold E
AE
Stütz
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036, Graz, Austria.
Marion
M
Tschernutter
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036, Graz, Austria.
Werner
W
Windischhofer
Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
Stephen G
SG
Withers
D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016537:Gangliosidosis, GM1 / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors* / Q000235:genetics
D003517:Cyclopentanes; D004791:Enzyme Inhibitors; C021502:acid beta-galactosidase; D001616:beta-Galactosidase
Aminocyclopentane; Carbafuranose; G(M1)-Gangliosidosis; Galactosidase inhibitor; Pharmacological chaperone