3,4,5-Trihydroxypiperidine Based Multivalent Glucocerebrosidase (GCase) Enhancers.

Chembiochem

Dipartimento di Chimica "Ugo Schiff" DICUS, Università di Firenze, Via della Lastruccia 3-13, 50019, Sesto, Fiorentino (FI), Italy.

Published: June 2022

The synthesis of five new multivalent derivatives of a trihydroxypiperidine iminosugar was accomplished through copper catalyzed alkyne-azide cycloaddition (CuAAC) reaction of an azido ending piperidine and several propargylated scaffolds. The resulting multivalent architectures were assayed as inhibitors of lysosomal GCase, the defective enzyme in Gaucher disease. The multivalent compounds resulted in much more potent inhibitors than a parent monovalent reference compound, thus showing a good multivalent effect. Biological investigation of these compounds as pharmacological chaperones revealed that the trivalent derivative (12) gives a 2-fold recovery of the GCase activity on Gaucher patient fibroblasts bearing the L444P/L444P mutations responsible for neuropathies. Additionally, a thermal denaturation experiment showed its ability to impart stability to the recombinant enzyme used in therapy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9400994PMC
http://dx.doi.org/10.1002/cbic.202200077DOI Listing

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