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Crystal structure of the inclusion complex of cholesterol in ?-cyclodextrin and molecular dynamics studies.

ABSTRACT: The role of beta-cyclodextrin (?-CD) in cholesterol removal primarily from mammalian cells and secondly from dairy products has been studied thoroughly in recent years. Although the physicochemical characterization of the inclusion compound of cholesterol in ?-CD has been achieved by various methods, no crystal structure has been determined so far. We report here the crystal structure of the inclusion compound of cholesterol in ?-CD. The inclusion complex crystallizes in the triclinic space group P1 forming head-to-head dimers which are stacked along the c-axis. One well-defined cholesterol molecule 'axially' encapsulated inside the ?-CD dimer and 22 water molecules that stabilize the complexes in the crystalline state comprise the asymmetric unit of the structure. The dimers are arranged in an intermediate (IM) channel packing mode in the crystal. Moreover, MD simulations, at 300 and 340 K, based on the crystallographically determined coordinates of the complex show that the formed cholesterol/?-CD inclusion compound remains very stable in aqueous solution at both temperatures.

SUBMITTER: Christoforides E

PROVIDER: S-EPMC5905284 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Crystal structure of the inclusion complex of cholesterol in β-cyclodextrin and molecular dynamics studies.

Christoforides Elias E Papaioannou Andreas A Bethanis Kostas K

Beilstein journal of organic chemistry 20180411

The role of beta-cyclodextrin (β-CD) in cholesterol removal primarily from mammalian cells and secondly from dairy products has been studied thoroughly in recent years. Although the physicochemical characterization of the inclusion compound of cholesterol in β-CD has been achieved by various methods, no crystal structure has been determined so far. We report here the crystal structure of the inclusion compound of cholesterol in β-CD. The inclusion complex crystallizes in the triclinic space grou ...[more]

PMID: 29719578

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Project description:BackgroundFlunarizine 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.ResultsThe structural assignments of FLN and β-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, β-CD and their mixtures confirmed the formation of β-CD-FLN inclusion complex in solution. 1H NMR titration data for β-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 β-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 β-CD cavity. The possible geometrical structures of the β-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the β-CD truncated cone.ConclusionNMR spectroscopic studies of FLN, β-CD and FLN:β-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 β-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of β-CD. The splitting of aromatic signals of FLN in the presence of β-CD suggests chiral differentiation of the guest FLN by β-CD.

Project description:Piroxicam (Px) is a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of osteoarthritis and rheumatoid arthritis. It is administered orally; however, its poor water solubility causes low loading to the nonconventional drug delivery systems (DDSs), such as electrospun fibers. Furthermore, the rapid dissolution of DDS and fast release of the embedded drugs are crucial for oral delivery of drugs to patients who are unconscious or suffering from dysphagia. In this regard, this study reports the development of rapidly dissolving cyclodextrin (CD)-based inclusion complex (IC) nanofibers by waterborne electrospinning for fast oral delivery of Px. Scanning electron microscopy analysis revealed the formation of bead-free fibers with a mean diameter range of 170-500 nm at various concentrations of Px; increasing the Px loading decreased the fiber diameter. The formation of IC was demonstrated by X-ray diffraction (XRD) analysis by the disappearance of crystalline peaks of Px. Likewise, differential scanning calorimetry (DSC) analysis showed the disappearance of the melting peak of the embedded Px due to IC formation. Both Fourier transform infrared (FTIR) and thermogravimetric analysis (TGA) confirmed the presence of Px within the fibers. 1H NMR experiments demonstrated Px preservation in the fibers after six months. Px-loaded nanofibers were employed for sublingual drug delivery. To mimic the environment of the mouth, the nanofibers were treated with artificial saliva, which revealed the instant dissolution of the nanofibers. Furthermore, dissolution experiments were performed on the tissues wetted with artificial saliva, where the dissolution of the fibers could be extended to a few seconds, demonstrating the suitability of the materials for sublingual oral drug delivery. Overall, this paper, for the first time, reports the rapid oral delivery of Px from polymer-free CD fibers produced by waterborne electrospinning without the requirement of any carrier polymer and toxic solvent.

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Crystal structure of the inclusion complex of cholesterol in ?-cyclodextrin and molecular dynamics studies.

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Crystal structure of the inclusion complex of cholesterol in β-cyclodextrin and molecular dynamics studies.

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