Get access

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

Authors

  • Andreas F. G. Glawar,

    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)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Dr. Daniel Best,

    1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford Mansfield Road, Oxford, OX1 3TA (UK)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Benjamin J. Ayers,

    1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford Mansfield Road, Oxford, OX1 3TA (UK)
    Search for more papers by this author
  • Saori Miyauchi,

    1. Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan)
    Search for more papers by this author
  • Shinpei Nakagawa,

    1. Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan)
    Search for more papers by this author
  • Matilde Aguilar-Moncayo,

    1. Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Profesor García González 1, 41012 Sevilla (Spain)
    Search for more papers by this author
  • Prof. José M. García Fernández,

    1. Instituto de Investigaciones Químicas, CSIC-Universidad de Sevilla, Américo Vespucio 49, Isla de la Cartuja, 41092 Sevilla (Spain)
    Search for more papers by this author
  • Prof. Carmen Ortiz Mellet,

    1. Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Profesor García González 1, 41012 Sevilla (Spain)
    Search for more papers by this author
  • Dr. Elizabeth V. Crabtree,

    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)
    Search for more papers by this author
  • Dr. Terry D. Butters,

    1. Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford, OX1 3QU (UK), Fax: (+44) 1865 285002
    Search for more papers by this author
  • Dr. Francis X. Wilson,

    1. Summit PLC, 91, Milton Park, Abingdon, Oxon OX14 4RY (UK)
    Search for more papers by this author
  • Prof. Atsushi Kato,

    1. Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan)
    Search for more papers by this author
  • Prof. George W. J. Fleet

    Corresponding author
    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)
    • Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford, OX1 3QU (UK), Fax: (+44) 1865 285002
    Search for more papers by this author

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.

Ancillary