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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.

Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N‐Alkylation on Hexosaminidase Inhibition

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  • Medientyp: E-Artikel
  • Titel: Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N‐Alkylation on Hexosaminidase Inhibition
  • Beteiligte: 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.
  • Erschienen: Wiley, 2012
  • Erschienen in: Chemistry – A European Journal
  • Sprache: Englisch
  • DOI: 10.1002/chem.201200110
  • ISSN: 0947-6539; 1521-3765
  • Schlagwörter: General Chemistry ; Catalysis ; Organic Chemistry
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The efficient scalable syntheses of 2‐acetamido‐1,2‐dideoxy‐<jats:sc>D</jats:sc>‐<jats:italic>galacto</jats:italic>‐nojirimycin (DGJNAc) and 2‐acetamido‐1,2‐dideoxy‐<jats:sc>D</jats:sc>‐<jats:italic>gluco</jats:italic>‐nojirimycin (DNJNAc) from <jats:sc>D</jats:sc>‐glucuronolactone, as well as of their enantiomers from <jats:sc>L</jats:sc>‐glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their <jats:italic>N</jats:italic>‐alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its <jats:italic>N</jats:italic>‐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 <jats:sc>L</jats:sc>‐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.</jats:p>