Synthesis, conformational analysis and glycosidase inhibition of bicyclic nojirimycin C-glycosides based on an octahydrofuro[3,2-b]pyridine motif - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Carbohydrate Research Année : 2022

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

Résumé

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 4C1 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
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hal-04542825 , version 1 (11-04-2024)

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Jérôme Désiré, Quentin Foucart, Ana Poveda, Gurvan Gourlaouen, Yuna Shimadate, et al.. Synthesis, conformational analysis and glycosidase inhibition of bicyclic nojirimycin C-glycosides based on an octahydrofuro[3,2-b]pyridine motif. Carbohydrate Research, 2022, 511, pp.108491. ⟨10.1016/j.carres.2021.108491⟩. ⟨hal-04542825⟩
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