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Bioorg Chem. 2019 May;86:652-664. doi: 10.1016/j.bioorg.2019.02.025. Epub 2019 Feb 12.

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

Author information

1
Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Prof. García González, 1, 41012-Seville, Spain.
2
Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Prof. García González, 1, 41012-Seville, Spain. Electronic address: anatere@us.es.
3
School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400, GA, United States.
4
Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
5
Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Prof. García González, 1, 41012-Seville, Spain. Electronic address: ajmoreno@us.es.

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.

KEYWORDS:

Chaperones; Click chemistry; Iminosugars; Protein crystallization; Pyrrolidines; Triazoles; β-glucocerebrosidase inhibitors

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