Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone: the effect of N-alkylation on hexosaminidase inhibition
| Autor: | Daniel Best, Benjamin James Ayers, George W. J. Fleet, Atsushi Kato, Saori Miyauchi, Shinpei Nakagawa, José M. García Fernández, Matilde Aguilar-Moncayo, Elizabeth V. Crabtree, Francis Xavier Wilson, Carmen Ortiz Mellet, Andreas F. G. Glawar, Terry D. Butters |
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| Rok vydání: | 2012 |
| Předmět: |
1-Deoxynojirimycin
Alkylation Stereochemistry Oligosaccharides Stereoisomerism Glucuronates Catalysis chemistry.chemical_compound Structure-Activity Relationship Acetamides Structure–activity relationship Hexosaminidase Enzyme Inhibitors Glucuronolactone chemistry.chemical_classification Organic Chemistry General Chemistry Oligosaccharide Enzyme Hexosaminidases chemistry Biochemistry Enantiomer Hydrophobic and Hydrophilic Interactions Imino Pyranoses |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1521-3765 |
| Popis: | 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 ¿-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 ß-GlcNAcases and ß-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. |
| Databáze: | OpenAIRE |
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