Influence of Selective Deoxyfluorination on the Molecular Structure of Type-2 N-Acetyl lactosamine

N-acetyllactosamine is a common carbohydrate motif found in several biologically active glycans. This motif is a backbone for additional N- and O-glycans modifications and significantly influences their shape and biological functions. In this work, we have systematically studied type 2 N-acetyllactosamine using a complete set of its monodeoxyfluorinated analogs. These fluorinated glycomimetics were studied using computational methods, X-ray crystallography, and NMR-based techniques, which revealed that some intramolecular inter-residue hydrogen bonds (O5′···H-O3, O2′-H···O6 and O6′-H···O3) fine-tune the conformational behavior of N-acetyllactosamine.

Deoxyfluorination of positions 2′ and 3 resulted in a flexibilization of the glycosidic linkage, attributed to the weakening and disruption of the O5′···H−O3 hydrogen bond, respectively. In contrast, 3′- and 6′- deoxyfluorination resulted in a subtle conformational rigidification of the glycosidic linkage, associated with the strengthening of the O5′···H−O3 and O2′−H···O6 hydrogen bonds in solution. The 3-deoxyfluorinated analog also showed an anomaly in the conformational behavior of the exocyclic hydroxyl 6′, indicating the presence of the O6′−H···O3 hydrogen bond in the solution. Furthermore, a combination of NMR analysis and COSMO-RS in silico calculations indicated that hydroxyls at positions 2′ and 6 are significantly more solvated than those at position 3, reflecting the previously reported lipophilicity trends.

In summary, this work demonstrates that selective deoxyfluorination of carbohydrates can be used to modulate their conformational behavior and lipophilicity. Moreover, our detailed conformational analysis and lipophilicity rationalization will serve as a guideline in the development of novel tailored LacNAc-derived glycomimetics with biomedical potential. This work was performed in the Research Group of Bioorganic Chemistry and Biomaterials under the supervision of Dr. Jindřich Karban, and in collaboration with research institutions, including The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB, Prague), The Center for Biological Research of the Spanish National Research Council (CIB, Madrid), and The Center for Cooperative Research in Biosciences of the Basque Research and Technology Alliance (CIC bioGUNE, Bilbao).

• Kurfiřt M.*, Červenková Šťastná L., Dračínský M., Pohl R., Císařová I., Sýkora J., Balouch M., Baka M., Hamala V., Cañada F.J., Ardá A., Jimenéz-Barbero J., Karban J.: Influence of Selective Deoxyfluorination on the Molecular Structure of Type-2 N-Acetyllactosamine. J. Org. Chem. 2024, 89(17), 11875-11890. doi: 10.1021/acs.joc.4c00879