title: 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.
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.
authors.affiliation: Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Thonhofer
authors.affiliation: Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weber
authors.affiliation: Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Andres Gonzalez
authors.initials: AG
authors.lastname: Santana
authors.affiliation: Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria.
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Pabst
authors.affiliation: Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria.
authors.forename: Eduard
authors.initials: E
authors.lastname: Paschke
authors.affiliation: Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schalli
authors.affiliation: Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria. Electronic address: stuetz@tugraz.at.
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Stütz
authors.affiliation: Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Tschernutter
authors.affiliation: Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Windischhofer
authors.affiliation: Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016537:Gangliosidosis, GM1 / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; C098432:isofagomine; D001616:beta-Galactosidase
keywords: 4-epi-Isofagomine; G(M1)-gangliosidosis; Galactosidase inhibitor; Iminoalditol; Pharmacological chaperone