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Synthesis, Kinetic Evaluation and Cell-Based Analysis of C-Alkylated Isofagomines as Chaperones of β-Glucocerebrosidase

Authors

  • Tara Hill,

    1. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1 (Canada)
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  • Dr. Michael B. Tropak,

    1. Division Genetics and Genome Biology, Hospital for Sick Children Institution, 555 University Avenue, Toronto, ON, M5G 1X8 (Canada)
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  • Dr. Don Mahuran,

    1. Division Genetics and Genome Biology, Hospital for Sick Children Institution, 555 University Avenue, Toronto, ON, M5G 1X8 (Canada)
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  • Dr. Stephen G. Withers

    Corresponding author
    1. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1 (Canada)
    • Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1 (Canada)
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Abstract

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Heat protection: A series of C-alkylated isofagomines were synthesised and tested as inhibitors of the human glucocerebrosidase. Nanomolar and subnanomolar competitive inhibition was seen in each case, and all served to stabilise the enzyme against thermal denaturation (see figure). Pharmacologically useful levels of chaperoning of enzyme activity were seen in all cases, particularly for the propyl and nonyl derivatives.

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