Synthesis of C-5a-chain extended derivatives of 4-epi-isofagomine: Powerful β-galactosidase inhibitors and low concentration activators of GM1-gangliosidosis-related human lysosomal β-galactosidase

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

doi:10.1016/j.bmcl.2016.01.059

Synthesis of C-5a-chain extended derivatives of 4-epi-isofagomine: Powerful β-galactosidase inhibitors and low concentration activators of GM1-gangliosidosis-related human lysosomal β-galactosidase

Bioorg Med Chem Lett. 2016 Mar 1;26(5):1438-42. doi: 10.1016/j.bmcl.2016.01.059. Epub 2016 Jan 22.

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 V6T 1Z1, Canada.
³ Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
⁴ Laboratory of Metabolic Diseases, Department of Pediatrics, 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: 26838810
DOI: 10.1016/j.bmcl.2016.01.059

Abstract

From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful β-d-galactosidase inhibitor 4-epi-isofagomine have become available. New compounds exhibit improved inhibitory activities comparable to benchmark compound NOEV (N-octyl-epi-valienamine) and may serve as leads towards improved and more selective pharmacological chaperones for GM1-gangliosidosis.

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

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Gangliosidosis, GM1 / enzymology*
Gangliosidosis, GM1 / pathology
Humans
Imino Pyranoses / chemical synthesis
Imino Pyranoses / chemistry
Imino Pyranoses / pharmacology*
Lysosomes / drug effects
Lysosomes / enzymology*
Models, Molecular
Molecular Structure
Structure-Activity Relationship
beta-Galactosidase / antagonists & inhibitors*
beta-Galactosidase / metabolism

Substances

Enzyme Inhibitors
Imino Pyranoses
isofagomine
beta-Galactosidase

Grants and funding

P 24815/FWF_/Austrian Science Fund FWF/Austria