Strengthening an Intramolecular Non-Classical Hydrogen Bond to Get in Shape for Binding.
Angew Chem Int Ed Engl
; 63(42): e202406024, 2024 Oct 14.
Article
in En
| MEDLINE
| ID: mdl-39072885
ABSTRACT
In this research article, we report on the strengthening of a non-classical hydrogen bond (C-Hâ
â
â
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 Lewisx (1, sLex). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre-organization of sLex 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 7.4â
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 14.9â
kJ mol-1, i.e., an improved pre-organization in the bioactive conformation. For a series of glycomimetics of sLex (1), this outcome could be confirmed by high field NMR-shifts of the H-C5Fuc, 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 CF3-group beneficially influences the pharmacokinetic properties of sLex mimetics. Thus, acid-stability, a prerequisite for gastrointestinal stability, could be substantially improved.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hydrogen Bonding
Language:
En
Journal:
Angew Chem Int Ed Engl
Year:
2024
Document type:
Article
Affiliation country:
Switzerland
Country of publication:
Germany