Selectively Deoxyfluorinated N‐Acetyllactosamine Analogues as ¹⁹F NMR Probes to Study Carbohydrate‐Galectin Interactions

Abstract

Galectins are widely expressed galactose-binding lectins implied, for example, in immune regulation, metastatic spreading, and pathogen recognition. N-Acetyllactosamine (Galβ1-4GlcNAc, LacNAc) and its oligomeric or glycosylated forms are natural ligands of galectins. To probe substrate specificity and binding mode of galectins, we synthesized a complete series of six mono-deoxyfluorinated analogues of LacNAc, in which each hydroxyl has been selectively replaced by fluorine while the anomeric position has been protected as methyl β-glycoside. Initial evaluation of their binding to human galectin-1 and -3 by ELISA and 19 F NMR T 2 -filter revealed that deoxyfluorination at C3, C4' and C6' completely abolished binding to galectin-1 but very weak binding to galectin-3 was still detectable. Moreover, deoxyfluorination of C2' caused an approximately 8-fold increase in the binding affinity towards galectin-1, whereas binding to galectin-3 was essentially not affected. Lipophilicity measurement revealed that deoxyfluorination at the Gal moiety affects log P very differently compared to deoxyfluorination at the GlcNAc moiety.

Synthesis of fluoro- and seleno-containing d-lactose and d-galactose analogues

“…For the synthesis of compound 4, acetobromogalactose 12 was treated with selenourea in acetone under reflux, as described by Kumar et al for D-glucopyranosyl bromide, 39 to form the corresponding D-galactosylselenyl transfer reagent 13 in 73% yield (Scheme 3). The presence of a characteristic 13 C NMR peak at 165.0 ppm for the isoselenouronium carbon and the concurrent shift at 79.7 ppm of the C-1 signal, confirmed the formation of the desired selenouronium moiety. Treatment of galactosyl bromide 12 with activated Zn powder in acetic acid/water gave the corresponding D-galactal in a 69% yield via a reductionelimination process.…”

The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates

“…Clearly this is an area with great future perspectives, especially as new glycosyl formation methodologies become available. The first lipophilicities of disaccharides have only recently been reported by the Karban group . It will also be of interest to explore whether glycan conformation will be significantly influenced by polyfluorination.…”

“…The first lipophilicities of disaccharides have only recently been reported by the Karban group. 523 It will also be of interest to explore whether glycan conformation 524 will be significantly influenced by polyfluorination.…”

Decoding Strategies to Evade Immunoregulators Galectin-1, -3, and -9 and Their Ligands as Novel Therapeutics in Cancer Immunotherapy

“…In one recent report, a QSAR has been derived from a library of 136 compounds containing analogs with C3′ and O3′ modifications to help identify a potent, selective inhibitor of Gal-3 binding [ 148 , 149 ]. Interestingly, the results from Kurfirt et al help identify new multivalent fluorinated sugars, which can abrogate Gal-1 binding, via the deoxyfluorination of -OH residues at carbon positions 3′, 4′, and 6′ of the LacNAc scaffold [ 150 ].…”