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- Title
Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N-Alkylation on Hexosaminidase Inhibition.
- Authors
Glawar, Andreas F. G.; Best, Daniel; Ayers, Benjamin J.; Miyauchi, Saori; Nakagawa, Shinpei; Aguilar-Moncayo, Matilde; García Fernández, José M.; Ortiz Mellet, Carmen; Crabtree, Elizabeth V.; Butters, Terry D.; Wilson, Francis X.; Kato, Atsushi; Fleet, George W. J.
- Abstract
The efficient scalable syntheses of 2-acetamido-1,2-dideoxy- D- galacto-nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy- D- gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of β-GlcNAcases and β-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics.
- Publication
Chemistry - A European Journal, 2012, Vol 18, Issue 30, p9341
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201200110