Conformational Change in the Mechanism of Inclusion of Ketoprofen in β-Cyclodextrin: NMR Spectroscopy, Ab Initio Calculations, Molecular Dynamics Simulations, and Photoreactivity.
Inclusion of drugs in cyclodextrins (CDs) is a recognized tool for modifying several properties such as solubility, stability, bioavailability, and so on. The photoreactive behavior of the β-CD/ketoprofen (KP) complex upon UV exposure showed a significant increase in photodecarboxylation, whereas the secondary degradation products by hydroxylation of the benzophenone moiety were inhibited. The results may account for an improvement of KP photophysical properties upon inclusion, thus better fostering its topical use. To correlate the structural details of the inclusion with these results, an NMR spectroscopic study of KP upon inclusion in β-CD was performed. Effects of the magnetically anisotropic centers of KP, changing their orientations upon inclusion and giving chemical shift variations, were specifically correlated with the results of the molecular dynamic simulations and ab initio calculations. In the large variety of papers focusing on the structural analysis of β-CD complexes, this work represents one of the few examples in which a detailed analysis of these simultaneous upfield-downfield NMR shifts of the same aromatic molecule upon inclusion is reported. Interestingly, the results demonstrate that the observed upfield and downfield shifts upon inclusion are not related to any direct magnetic role of β-CD. The conformational change of KP upon the inclusion process consists of a slight reduction in the angle between the two phenyl rings and in a remarkable reduction in the mobility of the carboxyl group, the latter being one of the main contributions to the NMR resonance shifts. These structural details help in understanding the features of the inclusion complex and, eventually, the driving force for its formation.
C4T (Colosseum Combinatorial Chemistry Centre for Technology) S.C.a r.l. , Via della Ricerca Scientifica s.n.c., 00133 Rome, Italy.
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Guzzo
Department of Chemical Science and Technology, University of Rome "Tor Vergata" , 00133 Rome, Italy.
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Mandaliti
Department of Chemical Science and Technology, University of Rome "Tor Vergata" , 00133 Rome, Italy.|Department of Chemical Pharmaceutical and Biomolecular Technologies, Faculty of Pharmacy Catholic University "Our Lady of Good Counsel" , Rr. D. Hoxha, 1000 Tirane, Albania.
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Nepravishta
Department of Discovery, Dompé Farmaceutici SpA Research Center , Via Campo di Pile, 67100 L'Aquila, Italy.
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Aramini
Department of Chemistry, University of Rome "Sapienza" , 00133 Rome, Italy.
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Bodo
Department of Physical and Chemical Sciences, University of L'Aquila , Via Vetoio (Coppito 1), 67010 L'Aquila, Italy.
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Daidone
Department of Discovery, Dompé Farmaceutici SpA Research Center , Via Campo di Pile, 67100 L'Aquila, Italy.
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Allegretti
C4T (Colosseum Combinatorial Chemistry Centre for Technology) S.C.a r.l. , Via della Ricerca Scientifica s.n.c., 00133 Rome, Italy.
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Topai
Department of Chemical Science and Technology, University of Rome "Tor Vergata" , 00133 Rome, Italy.
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Paci