Crystal and molecular structure of beta-cyclodextrins functionalized with the anti-inflammatory drug Etodolac.
The conjugates of beta-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 D(2)O 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 beta-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 beta-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 beta-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 beta-CD molecules are arranged in columns; the macrocycles form a herring bone pattern, so that the cavity of each beta-CD molecule is closed at each end by neighboring molecules. Within the layers, the beta-CD macrocycles are held together by a complicated intermolecular hydrogen bond network, in which numerous water molecules and hydroxyl groups are involved.
Dipartimento di Scienze Chimiche, Università di Catania, 95125 Catania, Italy.
Antonino
A
Puglisi
Enrico
E
Rizzarelli
Graziella
G
Vecchio
Rosa
R
Iacovino
Ettore
E
Benedetti
Carlo
C
Pedone
Michele
M
Saviano
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017308:Etodolac / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D012996:Solutions; D013237:Stereoisomerism; D047392:beta-Cyclodextrins / Q000737:chemistry*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012996:Solutions; D047392:beta-Cyclodextrins; D017308:Etodolac