Synthesis, conformational analysis and glycosidase inhibition of bicyclic nojirimycin C-glycosides based on an octahydrofuro[3,2-b]pyridine motif.
Carbohydr Res
; 511: 108491, 2022 Jan.
Article
em En
| MEDLINE
| ID: mdl-34953389
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 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 ß-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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MEDLINE
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Imino Açúcares
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Glicosídeo Hidrolases
Idioma:
En
Ano de publicação:
2022
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Article