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Eur J Med Chem. 2017 Jan 27;126:160-170. doi: 10.1016/j.ejmech.2016.09.095. Epub 2016 Sep 29.

(5aR)-5a-C-Pentyl-4-epi-isofagomine: A powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B.

Author information

1
Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France.
2
Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.
3
Center for Molecular Diseases, Lausanne University Hospital, 1005 Lausanne, Switzerland.
4
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
5
Neuroscience, Psychology, Pharmacology and Child Health Department, University of Florence, 50139 Florence, Italy.
6
Neuroscience, Psychology, Pharmacology and Child Health Department, University of Florence, 50139 Florence, Italy; Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy.
7
Dorphan, EPFL Innovation Park, 1015 Lausanne, Switzerland.
8
Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France. Electronic address: olivier.martin@univ-orleans.fr.

Abstract

This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal β-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human β-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50 = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant β-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell lines and activity restoration up to 91% of normal. Altogether, these results indicated that (5aR)-5a-C-pentyl-4-epi-isofagomine constitutes a promising PC-based drug candidate for the treatment of GM1-gangliosidosis and Morquio disease type B.

KEYWORDS:

GM1-gangliosidosis; Galactosidase inhibitors; Iminosugars; Morquio disease type B; Pharmacological chaperones

PMID:
27750150
DOI:
10.1016/j.ejmech.2016.09.095
[Indexed for MEDLINE]

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