title: A Morita-Baylis-Hillman based route to C-5a-chain-extended 4-epi-isofagomine type glycosidase inhibitors.
abstract: By Morita-Baylis-Hillman reaction of 2,3-O-isopropylidene-D-glyceraldehyde with α,β-unsaturated carbonyl as well as hetero analogous carbonyl compounds such as acrylonitrile, suitable precursors of isofagomine and of 4-epi-isofagomine are available. Elaboration of the structures by amine introduction, followed by intramolecular ring closure and subsequent hydroboration of the double bond provides 4-epi-isofagomine derivatives featuring chain extensions at C-5a which are determined by the structures of the carbonyl compounds employed. As an example, the synthesis of C-(5aR)- and C-(5aS)-5a-C-pentyl-4-epi-isofagomines, powerful inhibitors of β-galactosidases, is outlined. In line with reported data, the (C-5aR) epimer was found a highly potent experimental pharmacological chaperone for GM1-associated human lysosomal β-galactosidase mutant R201C.
authors.affiliation: Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010, Graz, Austria.
authors.forename: René
authors.initials: R
authors.lastname: Lebl
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: Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Tysoe
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: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weber
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. 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*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000201:enzymology; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; C098432:isofagomine; D006026:Glycoside Hydrolases
keywords: 4-epi-isofagomine; Glycosidase inhibitor; Morita-Baylis-Hillman reaction; Pharmacological chaperone