A remarkable change in inhibition potency and selectivity of isofagomine by simple N-modification

• Published in: Monatshefte für Chemie
• Main Authors: Culum, André, Prasch, Herwig, Dorn, Tobias, Fischer, Roland, Gardić, Ema, Schmutz, Franziska, Steinbrugger, Magdalena, Stütz, Arnold E., Weber, Patrick, Wrodnigg, Tanja M., Thonhofer, Martin
• Format: Journal Article
• Language: English
• Published: 29.05.2024
• ISSN: 0026-9247; 1434-4475
• DOI: 10.1007/s00706-024-03210-7

Abstract Herein, we present an alternative and elegant synthetic approach toward powerful β-glucosidase inhibitor isofagomine. Derivatizations of the ring nitrogen provided a selected set of N-modified isofagomine analogues. Biological evaluation of these compounds showed a remarkable change in potency as well as α/β-preference for various glycosidases from different sources when compared to the parent compound isofagomine. Overall, the conducted N-modification improved the potency against α-glucosidase from Saccharomyces cerevisiae (GH13). Coming along, significant diminished activities toward GH1 family β-glucosidases from three different sources have been observed for all tested derivatives. Moreover, and contrary to isofagomine, deactivations of β-galactosidase from Escherichia coli (GH2) as well as α-mannosidase from Canavalia ensiformis (GH38) have not been verified for this series of compounds. Graphical abstract