Synthesis of C-5a-substituted derivatives of 4-epi-isofagomine: notable β-galactosidase inhibitors and activity promotors of GM1-gangliosidosis related human lysosomal β-galactosidase mutant R201C

Martin Thonhofer; Patrick Weber; Andres Gonzalez Santana; Christina Tysoe; Roland Fischer; Bettina M Pabst; Eduard Paschke; Michael Schalli; Arnold E Stütz; Marion Tschernutter; Werner Windischhofer; Stephen G Withers

doi:10.1016/j.carres.2016.03.020

Synthesis of C-5a-substituted derivatives of 4-epi-isofagomine: notable β-galactosidase inhibitors and activity promotors of GM1-gangliosidosis related human lysosomal β-galactosidase mutant R201C

Carbohydr Res. 2016 Jun 24:429:71-80. doi: 10.1016/j.carres.2016.03.020. Epub 2016 Mar 31.

Affiliations

¹ Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
² Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1.
³ Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
⁴ Department of Pediatrics, Laboratory of Metabolic Diseases, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria.
⁵ Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria. Electronic address: stuetz@tugraz.at.

PMID: 27063389
DOI: 10.1016/j.carres.2016.03.020

Abstract

From an easily available partially protected analog of 1-deoxy-L-gulo-nojirimycin, by chain-branching at C-4 and suitable modification, lipophilic analogs of the powerful β-D-galactosidase inhibitor 4-epi-isofagomine have been prepared. New compounds exhibit considerably improved inhibitory activities when compared with the unsubstituted parent compound and may serve as leads toward new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

Keywords: 4-Epi-isofagomine; G(M1)-gangliosidosis; Galactosidase inhibitor; Iminoalditol; Pharmacological chaperone.

MeSH terms

1-Deoxynojirimycin / analogs & derivatives*
1-Deoxynojirimycin / chemistry
Gangliosidosis, GM1 / drug therapy
Humans
Hydrophobic and Hydrophilic Interactions
Imino Pyranoses / chemical synthesis*
Imino Pyranoses / chemistry
Mucopolysaccharidosis IV / drug therapy
beta-Galactosidase / antagonists & inhibitors*
beta-Galactosidase / chemistry

Substances

1-deoxy-gulonojirimycin
Imino Pyranoses
isofagomine
1-Deoxynojirimycin
beta-Galactosidase

Grants and funding

P 24815/FWF_/Austrian Science Fund FWF/Austria