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. (24th June 2016)

• Record Type: Journal Article
• Authors: Thonhofer, Martin; Weber, Patrick; Gonzalez Santana, Andres; Tysoe, Christina; Fischer, Roland; Pabst, Bettina M.; Paschke, Eduard; Schalli, Michael; Stütz, Arnold E.; Tschernutter, Marion; Windischhofer, Werner; Withers, Stephen G.
• Is Part Of: Carbohydrate research. Volume 429(2016)
• Page Start: 71
• Page End: 80
• Publication Date: 2016-06-24
• Subjects: Iminoalditol -- 4-Epi-isofagomine -- Galactosidase inhibitor -- Pharmacological chaperone -- GM1-gangliosidosis; Carbohydrates -- Periodicals; Chemistry, Organic -- Periodicals; Biochemistry -- Periodicals; Carbohydrates -- Periodicals; Chimie organique -- Périodiques; Glucides -- Périodiques; Biochemistry; Carbohydrates; Chemistry, Organic; Periodicals; Electronic journals; 507.78
• DOI: 10.1016/j.carres.2016.03.020
• Languages: English
• ISSNs: 0008-6215

Abstract

Graphical Abstract: Highlights: The first synthesis of (5a S )-chain extended 4-epi-isofagomines. New compounds are powerful β-galactosidase inhibitors. Residual human β-galactosidase activity of mutant R201C is enhanced up to 10-fold (at 2.5 µM). 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.