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Publication Abstract from PubMed

In this research article, we report on the strengthening of a non-classical hydrogen bond (C-H⋅⋅⋅O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E-selectin ligand sialyl Lewis(x) (1, sLe(x)). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre-organization of sLe(x) in its binding conformation. We have shown, that among the elements responsible for the pre-organization, the stabilization by a non-classical hydrogen bond between the H-C5 of l-fucose and the ring oxygen O5 of the neighboring d-galactose moiety is essential and yields 7.4 kJ mol(-1). This effect could be further strengthened by replacing l-fucose by 6,6,6-trifluoro-l-fucose leading to an improved non-classical H-bond of 14.9 kJ mol(-1), i.e., an improved pre-organization in the bioactive conformation. For a series of glycomimetics of sLe(x) (1), this outcome could be confirmed by high field NMR-shifts of the H-C5(Fuc), by X-ray diffraction analysis of glycomimetics co-crystallized with E-selectin as well as by isothermal titration calorimetry. Furthermore, the electron-withdrawing character of the CF(3)-group beneficially influences the pharmacokinetic properties of sLe(x) mimetics. Thus, acid-stability, a prerequisite for gastrointestinal stability, could be substantially improved.

Strengthening an Intramolecular Non-Classical Hydrogen Bond to Get in Shape for Binding.,Varga N, Smiesko M, Jiang X, Jakob RP, Wagner B, Muhlethaler T, Datwyler P, Zihlmann P, Rabbani S, Maier T, Schwardt O, Ernst B Angew Chem Int Ed Engl. 2024 Oct 14;63(42):e202406024. doi: , 10.1002/anie.202406024. Epub 2024 Sep 12. PMID:39072885^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.