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Strengthening an Intramolecular Non-Classical Hydrogen Bond to Get in Shape for Binding.
- Source :
-
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Oct 14; Vol. 63 (42), pp. e202406024. Date of Electronic Publication: 2024 Sep 12. - Publication Year :
- 2024
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Abstract
- 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 <superscript>x</superscript> (1, sLe <superscript>x</superscript> ). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre-organization of sLe <superscript>x</superscript> 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 <superscript>-1</superscript> . 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 <superscript>-1</superscript> , i.e., an improved pre-organization in the bioactive conformation. For a series of glycomimetics of sLe <superscript>x</superscript> (1), this outcome could be confirmed by high field NMR-shifts of the H-C5 <superscript>Fuc</superscript> , 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 <subscript>3</subscript> -group beneficially influences the pharmacokinetic properties of sLe <superscript>x</superscript> mimetics. Thus, acid-stability, a prerequisite for gastrointestinal stability, could be substantially improved.<br /> (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Details
- Language :
- English
- ISSN :
- 1521-3773
- Volume :
- 63
- Issue :
- 42
- Database :
- MEDLINE
- Journal :
- Angewandte Chemie (International ed. in English)
- Publication Type :
- Academic Journal
- Accession number :
- 39072885
- Full Text :
- https://doi.org/10.1002/anie.202406024