Exploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of β-glucocerebrosidase inhibition.

TitleExploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of β-glucocerebrosidase inhibition.
Publication TypeJournal Article
Year of Publication2019
AuthorsMartínez-Bailén, M, Carmona, AT, Patterson-Orazem, AC, Lieberman, RL, Ide, D, Kubo, M, Kato, A, Robina, I, Moreno-Vargas, AJ
JournalBioorg Chem
Volume86
Pagination652-664
Date Published2019 May
ISSN1090-2120
Abstract

The synthesis of a library of pyrrolidine-aryltriazole hybrids through CuAAC between two epimeric dihydroxylated azidomethylpyrrolidines and differently substituted phenylacetylenes is reported. The evaluation of the new compounds as inhibitors of lysosomal β-glucocerebrosidase showed the importance of the substitution pattern of the phenyl moiety in the inhibition. Crystallization and docking studies revealed key interactions of the pyrrolidine motif with aminoacid residues of the catalytic site while the aryltriazole moiety extended along a hydrophobic surface groove. Some of these compounds were able to increase the enzyme activity in Gaucher patient fibroblasts, acting as a new type of chemical chaperone for Gaucher disease.

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DOI10.1016/j.bioorg.2019.02.025
Alternate JournalBioorg. Chem.
PubMed ID30825709