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...

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Published in:Biopolymers 2009-12, Vol.91 (12), p.1227-1235
Main Authors: Puglisi, Antonino, Rizzarelli, Enrico, Vecchio, Graziella, Iacovino, Rosa, Benedetti, Ettore, Pedone, Carlo, Saviano, Michele
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents, Non-Steroidal - chemistry
anti-inflammatory drug
beta-Cyclodextrins - chemistry
Binding Sites
conformation
Crystallography, X-Ray
Etodolac
Etodolac - chemistry
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Structure
Protein Binding
Protein Conformation
Solutions
Stereoisomerism
X-ray diffraction
β-cyclodestrin conjugates
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Summary: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 Å 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
ISSN:0006-3525
1097-0282
DOI:10.1002/bip.21202