Iminosugar-based galactoside mimics as inhibitors of galactocerebrosidase: SAR studies and comparison with other lysosomal galactosidases.
Several families of iminosugar-based galactoside mimics were designed, synthesized, and evaluated as galactocerebrosidase (GALC) inhibitors. They were also tested as inhibitors of lysosomal β- and α-galactosidases in order to find new potent and selective pharmacological chaperones for treatment of the lysosomal storage disorder, Krabbe disease. Whereas 1-C-alkyl imino-L-arabinitols are totally inactive toward the three enzymes, 1-C-alkyl imino-D-galactitols were found to be active only toward α-galactosidase A. Finally, 1-N-iminosugars provided the best results, as 4-epi-isofagomine was found to be a good inhibitor of both lysosomal β-galactosidase and GALC. Further elaboration of this structure is required to achieve selectivity between these two galactosidases.
Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Université d'Orléans & CNRS, Rue de Chartres, BP 6759, 45067 Orléans cedex 2 (France).
Anna
A
Biela-Banaś
Farah
F
Oulaïdi
Sophie
S
Front
Estelle
E
Gallienne
Kyoko
K
Ikeda-Obatake
Naoki
N
Asano
David A
DA
Wenger
Olivier R
OR
Martin
D005697:Galactosides / Q000737:chemistry*; D005698:Galactosylceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D050112:Imino Pyranoses / Q000037:antagonists & inhibitors / Q000378:metabolism; D050111:Imino Sugars / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D007965:Leukodystrophy, Globoid Cell / Q000188:drug therapy; D008247:Lysosomes / Q000201:enzymology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D005697:Galactosides; D050112:Imino Pyranoses; D050111:Imino Sugars; C098432:isofagomine; D000519:alpha-Galactosidase; D001616:beta-Galactosidase; D005698:Galactosylceramidase
Krabbe disease; galactocerebrosidase; iminosugars; inhibitors; pharmacological chaperones