Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone: the effect of N-alkylation on hexosaminidase inhibition.
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.
Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Andreas F G
AF
Glawar
Daniel
D
Best
Benjamin J
BJ
Ayers
Saori
S
Miyauchi
Shinpei
S
Nakagawa
Matilde
M
Aguilar-Moncayo
José M
JM
García Fernández
Carmen
C
Ortiz Mellet
Elizabeth V
EV
Crabtree
Terry D
TD
Butters
Francis X
FX
Wilson
Atsushi
A
Kato
George W J
GW
Fleet
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry*; D000478:Alkylation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005965:Glucuronates / Q000737:chemistry*; D006596:Hexosaminidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D050112:Imino Pyranoses / Q000737:chemistry*; D009844:Oligosaccharides / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C576449:2-acetamido-1,2-dideoxy-D-galacto-nojirimycin; C576450:2-acetamido-1,2-dideoxy-D-gluco-nojirimycin; D000081:Acetamides; D004791:Enzyme Inhibitors; D005965:Glucuronates; D050112:Imino Pyranoses; D009844:Oligosaccharides; D017485:1-Deoxynojirimycin; C004940:glucuronolactone; D006596:Hexosaminidases