Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N‐Alkylation on Hexosaminidase Inhibition |
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| Authors: | Andreas F. G. Glawar Dr. Daniel Best Benjamin J. Ayers Saori Miyauchi Shinpei Nakagawa Matilde Aguilar‐Moncayo Prof. José M. García Fernández Prof. Carmen Ortiz Mellet Dr. Elizabeth V. Crabtree Dr. Terry D. Butters Dr. Francis X. Wilson Prof. Atsushi Kato Prof. George W. J. Fleet |
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| Affiliation: | 1. Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford, OX1 3QU (UK), Fax: (+44)?1865?285002;2. Chemistry Research Laboratory, Department of Chemistry, University of Oxford Mansfield Road, Oxford, OX1 3TA (UK);3. Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930‐0194 (Japan);4. Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Profesor García González 1, 41012 Sevilla (Spain);5. Instituto de Investigaciones Químicas, CSIC‐Universidad de Sevilla, Américo Vespucio 49, Isla de la Cartuja, 41092 Sevilla (Spain);6. Summit PLC, 91, Milton Park, Abingdon, Oxon OX14 4RY (UK) |
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| 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. |
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| Keywords: | carbohydrates cell penetration inhibitors iminosugars oligosaccharides |
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