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Inclusion complexes of ?-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

ABSTRACT: Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with ?-cyclodextrin (?-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/?-CD and 2/?-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and in the solid state from single-crystal X-ray diffraction of 1/?-CD and 2/?-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule.

SUBMITTER: Castiglione F

PROVIDER: S-EPMC5405689 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Inclusion complexes of β-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

Castiglione Franca F Ganazzoli Fabio F Malpezzi Luciana L Mele Andrea A Panzeri Walter W Raffaini Giuseppina G

Beilstein journal of organic chemistry 20170413

Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with β-cyclodextrin (β-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/β-CD and 2/β-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features ma ...[more]

PMID: 28503206

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Project description:BACKGROUND:Flunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state. RESULTS:The structural assignments of FLN and ?-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, ?-CD and their mixtures confirmed the formation of ?-CD-FLN inclusion complex in solution. 1H NMR titration data for ?-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of K a = 157 M-1 and change in Gibbs free energy of ?G?=?- 12.65 kJ mol-1. The binding constant of the ?-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the ?-CD cavity. The possible geometrical structures of the ?-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the ?-CD truncated cone. CONCLUSION:NMR spectroscopic studies of FLN, ?-CD and FLN:?-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into ?-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of ?-CD. The splitting of aromatic signals of FLN in the presence of ?-CD suggests chiral differentiation of the guest FLN by ?-CD.

Dataset Information

Inclusion complexes of ?-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

Publications

Inclusion complexes of β-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

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