title: Structure and stability of warfarin-sodium inclusion complexes formed with permethylated monoamino-β-cyclodextrin.
abstract: Inclusion complexes of warfarin enantiomers with permethylated monoamino-β-cyclodextrin (PMMABCD) were characterized using CE and (1)H NMR spectroscopy in aqueous solution. These techniques gave complementary information on the stability and the structure of the diastereomeric host-guest inclusion complexes. The stability constants were determined from CE experiments in a wide pH range. Change in the migration order on the variation of the pH was observed. (1)H NMR assignments have been established for the seven non-equivalent carbohydrate units of the host in the complex at pH 7-9. Specific H-H distance restraints were obtained from NOESY experiments and were introduced into molecular modeling to establish the geometry of the inclusion complexes. It was found that the open side chain warfarin enters the cavity from the primary side of the CD. The orientation of the coumarin ring within the cavity has the same preference for the two warfarin enantiomers owing to an ionic interaction with the amino group of the CD. Accordingly, enantioselectivity at pH 8.5 arises from the difference in the CH/π interactions between warfarin aromatics and the manifold of CH groups of the CD.
authors.affiliation: Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest, Hungary. tarkanyi.gabor@ttk.mta.hu
authors.forename: Gábor
authors.initials: G
authors.lastname: Tárkányi
authors.forename: Krisztina
authors.initials: K
authors.lastname: Németh
authors.forename: Réka
authors.initials: R
authors.lastname: Mizsei
authors.forename: Orsolya
authors.initials: O
authors.lastname: Tőke
authors.forename: Júlia
authors.initials: J
authors.lastname: Visy
authors.forename: Miklós
authors.initials: M
authors.lastname: Simonyi
authors.forename: László
authors.initials: L
authors.lastname: Jicsinszky
authors.forename: Julianna
authors.initials: J
authors.lastname: Szemán
authors.forename: Lajos
authors.initials: L
authors.lastname: Szente
mesh_terms: D002241:Carbohydrates / Q000737:chemistry; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013329:Structure-Activity Relationship; D014859:Warfarin / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D002241:Carbohydrates; D047392:beta-Cyclodextrins; D014859:Warfarin