Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono‐ and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation‐optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C‐3 and C‐4 showed weaker affinities with LecA as compared to those with the fluorine atom at C‐2 or C‐6. This research has focused on the chemical synthesis of “drug‐like” low‐molecular‐weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions

Denavit

Lainé

Bouzriba

et al. 2019

“…[27] Thus, preparation of the trifluoromethansulfonate intermediate preceded nucleophilic fluorination with neat Et 3 N•3HFa llowing formation of compound 20 with complete retention of configuration, presumably via neighboringg roup participation of the benzyloxy at C-4. [28] The configurationo ft he fluorinea tom was ascertained based on 19 FNMR spectroscopy ( 19 FNMR (470 MHz): 2 J F-3,H3 = 45.9 Hz, 3 J F-3,H-2 = 3 J F-3,H-4 = 17.5 Hz). Directc leavage of the 1,6-anhydro bridge with BCl 3 furnished the desired 3-fluoroglucose 4 in 82 %y ield (a/b = 1:1i na cetone-d 6 ).…”

Section: Resultsmentioning

confidence: 99%

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

St‐Gelais

Côté

Lainé

et al. 2020

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.

“…Although the introduction of an anomeric F atom can influence the 4 C 1 / 1 C 4 equilibrium (see section 5.2), [64] in general, pyranosides fluorinated at non‐anomeric positions have been observed to adopt the same conformation as their non‐fluorinated counterparts [5a, 51, 65] . Their solution‐state conformation is best evaluated by using NMR spectroscopy, as several different coupling constants ( 2 J C,F , 3 J H,H , 3 J H,F , 3 J C,F ) provide critical confirmation of both the position of fluorination and ring conformation [54a, 64–66] . A recent review by Linclau et al.…”

Section: Conformational Distortion and Plasticitymentioning

confidence: 99%

The Role of Fluorine in Glycomimetic Drug Design

Hevey

2020

Glycans are well established to play important roles at various stages of infection and disease, and ways to modulate these interactions have been sought as novel therapies. The use of native glycan structures has met with limited success, which can be attributed to their characteristic high polarity (e.g., low binding affinities) and inherently poor pharmacokinetic properties (e.g., short drug–target residence times, rapid renal excretion), leading to the development of ′glycomimetics′. Fluorinated drugs have become increasingly common over recent decades, with fluorinated glycomimetics offering some unique advantages. Deoxyfluorination maintains certain electrostatic interactions, while concomitantly reducing net polarity through ′polar hydrophobicity′, improving residence times and binding affinities. Fluorination destabilizes the oxocarbenium transition state associated with metabolic degradation, and can restore exo‐ and endo‐anomeric effects in C‐glycosides and carbasugars. Lastly, it has shown great utility in radiotracer development and enhancement of antigenicity in glycan‐based vaccines. Owing to synthetic challenges, fluorinated glycomimetics have been somewhat underutilized to date, but methodological improvements will advance their use in glycomimetic drugs.