Addressing the Structural Complexity of Fluorinated Glucose Analogues: Insight into Lipophilicities and Solvation Effects

Abstract

In this work,w es ynthesized all mono-, di-, and trifluorinated glucopyranose analogues at positions C-2, C-3, C-4, and C-6. This systematic investigation allowed us to perform direct comparison of 19 Fr esonances of fluorinated glucose analoguesa nd also to determine their lipophilicities. Compounds with af luorine atom at C-6 are usually the most hydrophilic, whereas those with vicinal polyfluorinated motifs are the most lipophilic. Finally, the solvation energies of fluorinated glucosea naloguesw ere assessed for the first time by using density functional theory.T hism ethoda llowedt he log P prediction of fluoroglucose analogues, whichw as comparable to the Clog P valueso btained from various web-basedp rograms.

The Role of Fluorine in Glycomimetic Drug Design

“…1,2‐Dideoxy‐1,2‐difluorinated glucose was first reported as an improved ligand for glycogen phosphorylase, with an observed affinity that was higher than expected based on the cumulative increases afforded by the two mono‐deoxyfluoro derivatives [5a] . Subsequent studies have similarly reported on various di‐deoxyfluoro, [53f, 54] tri‐deoxyfluoro, [25a, 51, 53f, 55] and tetra‐deoxyfluoro [25a, 55b] glycomimetic derivatives with significantly enhanced affinities.…”

“…In comparing tri‐deoxytrifluoro derivatives, compounds with all‐ cis configured F atoms were the least hydrophobic (Tal, −0.84), presumably a result of their larger molecular dipole [51] . Another recent study performed a comprehensive systematic comparison of mono‐, di‐, and tri‐deoxyfluorinated Glc derivatives, where it was observed that vicinal fluorination afforded the most lipophilic compounds, likely as a result of their greater reduction in polar surface area [53f] . Calculated free energies of solvation correlated well to the experimentally determined log P values.…”

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

“…We first evaluated reduction conditions on a simpler difluorinated hexopyranose analogue. Thus, difluoroglucose 21, easily accessible in 3 steps from levoglucosan (1) [21], was subjected to lithium aluminium hydride (LiAlH 4 ) in THF (Scheme 1a) and difluoroglucitol 22 was isolated in 58% yield. The reaction was hardly reproducible because a thick gel was formed after neutralisation with an acidic resin, thus resulting in yield loss after a difficult filtration.…”

“…Our group is interested in the synthesis, physical properties and biological activities of heavily fluorinated carbohydrates [19,[21][22][23][24][25]. With intermediates 2-5 in hand, we studied the reactivities of a small set of chirally distinct difluorinated 1,6-anhydro-β-ᴅ-hexopyranose analogues.…”

Fluorinated Carbohydrates as Lectin Ligands: Simultaneous Screening of a Monosaccharide Library and Chemical Mapping by 19F NMR Spectroscopy

“… 22 − 24 Additionally, its particular physicochemical properties 25 introduce electronic and polar-hydrophobic effects. 26 Indeed, fluorine modulates the population of the conformational space 27 , 28 and lipophilicity of fluorine-containing carbohydrates. 29 Smart use of these features has already allowed development of new molecules that efficiently act as substrates 30 and inhibitors of glycosidases.…”