Non-Stick Sugars: Synthesis of Difluorosugar Fluorides as Potential Glycosidase Inactivators

Abstract

Four new difluorosugar fluorides, 2-deoxy-2,5-difluoro-α-l-idopyranosyl fluoride, 1,5-difluoro-d-glucopyranosyl fluoride, 1,5-difluoro-l-idopyranosyl fluoride, and 2-deoxy-1,2-difluoro-d-glucopyranosyl fluoride, were synthesized from known precursors by a radical bromination/fluoride displacement sequence, followed by deprotection. The compounds were tested as time-dependent inactivators of the β-glucosidase from Agrobacterium sp. (Abg, EC 3.2.1.21) and, while they were shown to bind to the enzyme active site as reversible competitive inhibitors, the only time-dependent inactivation observed was traced to the presence of an extremely small amount (<0.1%) of a highly reactive contaminating impurity.

Synthesis and Lipophilicity of Trifluorinated Analogues of Glucose

“…Also, the group of Cerny included the preparation of 2,4-dideoxy-2,4-difluoroglucose 4 as part of their synthetic program related to the study of the reactivity of 1,6-anhydrohexopyranose derivatives . In 2009, the group of Withers prepared and investigated difluorosugar fluorides 5 and 6 analogues of glucose as inactivators of the β-glucosidase from Agrobacterium sp . Interestingly, they were shown to bind to the enzyme active site reversibly as competitive inhibitors.…”

Fluorosugars: synthesis of the 2,3,4-trideoxy-2,3,4-trifluoro hexose analogues of d-glucose and d-altrose and assessment of their erythrocyte transmembrane transport

“…1 and 2 have been reported. 6,7 There has been some recent interest in much more highly fluorinated sugar analogues. DiMagno et al have prepared hexafluorohexose analogues exemplified by 3.…”

Fluorinated carbohydrates as chemical probes for molecular recognition studies. Current status and perspectives

“…Indeed, the tetrafluorinated galactomimetic 6.15 was a substrate of galactose oxidase, with a loss of affinity compared to D-galactose. 168 Tetrafluorination of sugars has also been explored as a way to generate competitive enzyme inhibitors. As leading examples, glucose analogues 6.16 and 6.17 have been investigated as b-glucosidase inactivators, 168 while the nucleotide-sugar analogue 6.18 strongly inhibited UDP-galactopyranose mutase (UGM) from Mycobacterium tuberculosis.…”

“…168 Tetrafluorination of sugars has also been explored as a way to generate competitive enzyme inhibitors. As leading examples, glucose analogues 6.16 and 6.17 have been investigated as b-glucosidase inactivators, 168 while the nucleotide-sugar analogue 6.18 strongly inhibited UDP-galactopyranose mutase (UGM) from Mycobacterium tuberculosis. 89 Interestingly, as already mentioned in Section 4.3, molecule 6.18 displayed a better affinity for UGM than the two monofluorinated analogues at C-2 and C-3.…”