Crystal and molecular structure of β‐cyclodextrins functionalized with the anti‐inflammatory drug Etodolac

The conjugates of β-cyclodextrins with R- or with S-Etodolac were characterized by NMR spectroscopy, and S-Etodolac alone was characterized by X-ray diffraction analysis. In solution, the R-Etodolac conjugate is soluble in water; the other epimer shows a very low solubility. The NMR characterization of the R-Etodolac conjugate in D2O shows that, in aqueous solution, the Edotolac moiety is self-included in the cavity, while the NMR characterization in MeOH of both conjugates underlines that, in this solvent, the Etodolac moiety is not included in the CD cavity. The X-ray structure determination of the S-Etodolac conjugate reveals a “sleeping swan”-like shape, with the covalently bonded Etodolac moiety being folded with the 8-ethyl group inserted inside the hydrophobic cavity of the β-CD ring. The terminal methyl group of the 8-ethyl group enters the centre of cavity from the side of the primary hydroxyl groups and is buried inside the β-CD macrocycle. The terminal methyl group is positioned at a distance of 1.06 A from the O(4) plane in the side of the primary hydroxyl groups. In addition to van der Waals interactions between the hydrophobic ethyl group and the β-CD cavity, the folded conformation is further stabilized by one intramolecular H-bond involving the indole N–H group and the primary hydroxyl group of the glucose unit 7. Along the b axis, the β-CD molecules are arranged in columns; the macrocycles form a herring bone pattern, so that the cavity of each β-CD molecule is closed at each end by neighboring molecules. Within the layers, the β-CD macrocycles are held together by a complicated intermolecular hydrogen bond network, in which numerous water molecules and hydroxyl groups are involved. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 1227–1235, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com