Sankt Radegund bei Graz, Austria
Sankt Radegund bei Graz, Austria

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Schalli M.,University of Graz | Tysoe C.,University of British Columbia | Fischer R.,University of Graz | Pabst B.M.,Laboratory of Metabolic Diseases | And 7 more authors.
Carbohydrate Research | Year: 2017

From 1,2;3,4-di-O-isopropylidene-α-D-galactopyranose, a series of highly functionalized (hydroxymethyl)cyclopentanes was easily available. In line with reports by Reymond and Jäger on similar structures, these amine containing basic carbasugars are potent inhibitors of β-D-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for GM1-gangliosidosis-associated lysosomal acid β-galactosidase mutant R201C, thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease. © 2017 Elsevier Ltd


Lebl R.,University of Graz | Thonhofer M.,University of Graz | Tysoe C.,University of British Columbia | Pabst B.M.,Laboratory of Metabolic Diseases | And 7 more authors.
Carbohydrate Research | Year: 2017

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. © 2017 Elsevier Ltd


Thonhofer M.,University of Graz | Weber P.,University of Graz | Gonzalez Santana A.,University of British Columbia | Tysoe C.,University of British Columbia | And 8 more authors.
Carbohydrate Research | Year: 2016

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. © 2016 Elsevier Ltd.


Thonhofer M.,University of Graz | Weber P.,University of Graz | Santana A.G.,University of British Columbia | Fischer R.,University of Graz | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

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. © 2016 Elsevier Ltd. All rights reserved.


PubMed | University of British Columbia, University of Graz and Laboratory of Metabolic Diseases
Type: | Journal: Carbohydrate research | Year: 2016

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 -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.


PubMed | University of British Columbia, University of Graz and Laboratory of Metabolic Diseases
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016

From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful -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.

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