Synthesis, conformational analysis and glycosidase inhibition of bicyclic nojirimycin C-glycosides based on an octahydrofuro[3, 2-b]pyridine motif. (January 2022)

• Record Type: Journal Article
• Authors: Désiré, Jérôme; Foucart, Quentin; Poveda, Ana; Gourlaouen, Gurvan; Shimadate, Yuna; Kise, Maki; Proceviat, Cameron; Ashmus, Roger; Vocadlo, David J.; Jiménez-Barbero, Jesús; Kato, Atsushi; Blériot, Yves
• Is Part Of: Carbohydrate research. Volume 511(2022)
• Publication Date: 2022-01
• Subjects: Iminosugar -- Glycosidase -- Conformation -- Inhibition -- Bicycle -- Hexosaminidase; 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.2021.108491
• Languages: English
• ISSNs: 0008-6215

Abstract

Abstract: A set of bicyclic iminosugar C-glycosides, based on an octahydrofuro[3, 2-b]pyridine motif, has been synthesized from a C -allyl iminosugar exploiting a debenzylative iodocycloetherification and an iodine nucleophilic displacement as the key steps. The halogen allowed the introduction of a range of aglycon moieties of different sizes bearing several functionalities such as alcohol, amine, amide and triazole. In these carbohydrate mimics the fused THF ring forces the piperidine to adopt a flattened 4 C 1 conformation according to NMR and DFT calculations studies. In their deprotected form, these bicycles were assayed on a panel of 23 glycosidases. The iminosugars displaying hydrophobic aglycon moieties proved to be superior glycosidase inhibitors, leading to a low micromolar inhibition of human lysosome β-glucosidase (compound 11 ; IC50 = 2.7 μM) and rice α-glucosidase (compound 10 ; IC50 = 7.7 μM). Finally, the loose structural analogy of these derivatives with Thiamet G, a potent OGA bicyclic inhibitor, was illustrated by the weak OGA inhibitory activity (Ki = 140 μM) of iminosugar 5 . Graphical abstract: Image 1 Highlights: Bicyclic iminosugars disclosed to mimic the oxocarbenium character of hexosaminidases TS and the substrate assisted catalysis. synthetic methodology allows introduction of structural diversity at the aglycon moiety. Conformational analysis demonstrates a conformation close to the one observed for NAG thiazoline. Evaluation as glycosidase inhibitors leads to weak hexosaminidase but potent α-glucosidase inhibitors.