Β-cyclodextrin Cavity Research Articles

Polyrotaxane with π-conjugated porphyrin and polyazomethine systems prepared from a type of porphyrindialdehyde and complex of β-cyclodextrin with 1,4-phenylenediamine

The synthesis of 5,15-bis[4-(methoxycarbonyl)phenyl]-10,20-diphenylporphyrin (2) and its reduction to 5,15-bis[4-(hydroxymethyl)phenyl]-10,20-diphenylporphyrin (3), and so its oxidation to provide 5,15-bis(4-formylphenyl)-10,20-diphenylporphyrin (4) are reported. The copolymer possessing β-cyclodextrin (β-CD), π-conjugated porphyrin and polyazomethine systems was synthesized by the polycondensation of porphyrin-dialdehyde monomer (4) and β-cyclodextrin/1,4-phenylenediamine complex (5). The monomers and the copolymer were characterized by UV-Vis, 1H-NMR and IR spectra. Furthermore, 1H-NMR and FT-IR spectra confirmed locating the aromatic ring of 1,4-phenylenediamine molecule in the center of β-cyclodextrin cavity.

Effect of β-cyclodextrin on the behaviour of thermophysical and spectroscopic properties of binary mixtures of (isomeric butanediol + pyrrolidin-2-one)

Thermophysical parameters viz. excess molar volume VE, speed of sound u, viscosity η and spectroscopic parameters viz. FT-IR, 1H and 13C NMR have been measured for the ternary liquid mixtures of {isomeric butanediol (butane-1,2-diol, butane-1,3-diol, butane-1,4-diol, butane-2,3-diol)+pyrrolidin-2-one} in β-cyclodextrin over the whole composition range at T=308.15K. The deviation in the isentropic compressibility ΔκS, partial molar quantities QiE, deviation in viscosity Δη, deviation in Gibbs energy of activation for viscous flow g(x) and excess NMR chemical shift δE have been estimated and analysed. Results indicate that the position of hydroxyl groups of butanediol showed a noticeable effect on the thermophysical properties. Furthermore, the effect of addition of β-cyclodextrin caused significant changes, due to difference in the fitting of isomeric butanediol in the hydrophobic cavity of β-cyclodextrin. Particularly, visible changes in thermophysical properties of 1,4-BTD system have been observed in comparison to other isomers of BTD indicating that hydrogen bonding and affinity of fitting between (1,4-BTD and β-CD+PY) are greater than the other isomers. These results have been found to be in excellent concurrence with NMR and FT-IR studies. However, for 2,3-BTD and 1,3-BTD systems dispersion forces due to dissociation of self-associated PY and diols are predominant. The spectroscopic measurements (FT-IR, 1H and 13C NMR) confirm that the interaction between unlike molecules take place through hydroxyl groups of isomeric butanediol and carbonyl group of pyrrolidin-2-one.

Covalently Linked, Water-Dispersible, Cyclodextrin: Reduced-Graphene Oxide Sheets

Reduced-graphene oxide (rGO) sheets have been functionalized by covalently linking β-cyclodextrin (β-CD) cavities to the sheets via an amide linkage. The functionalized β-CD:rGO sheets, in contrast to rGO, are dispersible over a wide range of pH values (2-13). Zeta potential measurements indicate that there is more than one factor responsible for the dispersibility. We show here that planar aromatic molecules adsorbed on the rGO sheet as well as nonplanar molecules included in the tethered β-CD cavities have their fluorescence effectively quenched by the β-CD:rGO sheets. The β-CD:rGO sheets combine the hydrophobicity associated with rGO along with the hydrophobicity of the cyclodextrin cavities in a single water-dispersible material.

Regioselective N9 alkylation of purine rings assisted by β-cyclodextrin

Under the assistance of β-cyclodextrin, purine was effectively alkylated at N9 together with up to 99% conversion and good to excellent yield using water as the solvent. High regioselectivity-N9/N7 selectivity>99:1 was attributed to the β-cyclodextrin cavity blocked the N7 of purines ring.

Application of an inclusion complex for determination of dithianon residues in water and fruits

A 3,3′-benzidine/β-cyclodextrin fluorescence derivative (BCDFD) was prepared and characterized by means of elemental analysis and 1H NMR. An inclusion complex was formed between BCDFD and the pesticide dithianon based on the internal cavity of β-cyclodextrin (β-CD), and the binding constant (KS ) of the inclusion complex was investigated. The inclusion complex could be applied for the determination of dithianon residues. Based on this, a sensitive method for the determination of dithianon was established. The linear dynamic range was from 0.63 to 12.5 mg L−1 with a correlation coefficient of 0.9927. The limit of detection for an aqueous solution of standard and the relative standard deviation (RSD) were 10.6 µg L−1 and 0.76%, respectively. The proposed method has been successfully applied for the determination of dithianon residues in water and fruit samples with satisfactory results, and recoveries in the range of 96.0–108% were obtained. The method is rapid, direct, economical, and sensitive for dithianon analysis.

Proline–cyclodextrin conjugates: synthesis and evaluation as catalysts for aldol reaction in water

The synthesis of six conjugates of l-proline and β-cyclodextrin and their evaluation as catalysts of aldol reaction in water are described. The results indicated that the nature of the linker between proline and β-cyclodextrin is important for catalytic activity; the one with the most flexible linker gave the best results. Inhibition experiments showed that the cavity of β-cyclodextrin plays a role in the catalysis. Permethylation of the cyclodextrin hydroxyl groups led to higher conversion rates.

Host–guest interactions between dapsone and β-cyclodextrin (part I): study of the inclusion compound by nuclear magnetic resonance techniques

Dapsone (4,4′diaminodiphenylsulfone) is a very effective drug to treat leprosy and a broad range of infectious conditions such as Pneumocystis carinii pneumonia, toxoplasmosis and tuberculosis. However, the oral administration of this drug generally is related to serious side effects and treatment failures. It is believed that the inclusion compound of this drug and cyclodextrins would increase the wettability and the solubility of the encapsulated drug for a supported and gradual release, maximizing its biodisponibility over time. The encapsulation of dapsone in β-cyclodextrin was investigated by five nuclear magnetic resonance spectroscopy techniques. The data obtained for the complex in aqueous solution and in solid-state revealed a strong interaction between host and guest, showing that the drug molecule is deeply inserted in the CD cavity. The diffusion experiments (diffusion ordered spectroscopy) showed a high percentage of complexation (86 %) and that the drug molecule is preferentially interacting with the large side of the β-cyclodextrin cavity.

Release profiles of indometacin in β-cyclodextrin complexes from HPMC capsules

Powders containing indometacin complexed with β-cyclodextrin (1:1 ratio) obtained by two complexation methods (suspension/solution [with water removed by air stream, spray– and freeze–drying] and kneading techniques) were compared between them to observe the increase on the drug solubility and yield of the complexation process. The tests used for this comparison included the determination of the moisture content, true and bulk densities, angle of repose, Carr’s index and in vitro drug release (at pH 1.0) from HPMC capsules. In the dissolution tests the drug release was analyzed considering different parameters (similarity factor (f2), dissolution efficiency (DE) and the amounts released (Mt) at certain times (30, 60 and 180 min) by statistic analysis (α = 0.05)). The results obtained showed poor pharmaceutical properties for all mixtures and that the indometacin released from capsules containing inclusion complexes presented an increase on solubility when compared with reference formulation (lactose and microcrystalline cellulose instead of β-cyclodextrin). The release of indometacin showed no dependency on the amount of water used in the formation of the complexes being the differences observed mostly due to the characteristics of the particles, which were dependent on the complexation method. However the low yield of the complexation that occurred can be explained by the difference between the size of the drug molecule, the guest (diameter—7.5 A, length—14.2 A) and the size of the β-cyclodextrin cavity, the host (diameter—6.0–6.5 A).

Spectral and electrochemical study of host–guest inclusion complex between 2,4-dinitrophenol and β-cyclodextrin

The formation of host–guest inclusion complex of 2,4-dinitrophenol (2,4-DNP) with nano-hydrophobic cavity of β-cyclodextrin (β-CD) in solution phase was studied by UV–visible spectrophotometer and electrochemical method (cyclic voltammetry, CV). The prototropic behaviors of 2,4-DNP with and without β-CD and the ground state acidity constant (pKa) of host–guest inclusion complex (2,4-DNP–β-CD) were studied. The binding constant of inclusion complex at 303K was calculated using Benesi–Hildebrand plot and thermodynamic parameter (ΔG) was also calculated. The solid inclusion complex formation between β-CD and 2,4-DNP was confirmed by 1H NMR, FT-IR, XRD and SEM analysis. A schematic representation of this inclusion process is proposed by molecular docking studies using PatchDock server.

Modulation of dansyl moiety fluorescence in systems containing cyclodextrins

The present study reports on the changes in dansyl moiety fluorescence due to the interactions with the β-cyclodextrin cavity observed by steady-state fluorescence spectroscopy. First, the interaction of a guest molecule, dansyl-TEMPO (DT), which has in its structure a dansyl group as a fluorescent moiety and a paramagnetic fragment (TEMPO), with β-cyclodextrin was studied. Analysis of the EPR spectral parameters provided additional information on the host–guest interaction, suggesting that the cyclodextrin cavity accommodates dansyl rather than a TEMPO moiety. Second, the affinity between 1-adamantol or adamantane end-capped polyethylene glycols – A2Pnn – (as guests) and dansyl-β-cyclodextrin (D-β-CD, as a host) was investigated. In the presence of adamantol, the intensity of fluorescence of D-β-CD decreases and a hypsochromic effect was noticed. The same behaviour was observed in the presence of A2Pnn. Using Benesi–Hildebrand and Stern–Volmer equations and also the sensitivity factor made possible to obtain quantitative data on the interaction between the dansyl moiety and the cyclodextrin cavity. The formation of inclusion complexes in the solid state between D-β-CD and A2Pnn was evidenced analysing the DSC curves of the pure solids, physical mixture and prepared solid complexes. In addition, the use of D-β-CD for fluorescent labeling of a covalently based network hydrogel and diffusion of dansyl derivatives into a gel are shown as possible further application of this study.

The binding behavior of a helical column supramolecule formed by 6-deoxy-6-(2-pyrimidinethio)-β-cyclodextrin in both solution and the solid state

The mono-modified β-cyclodextrin, 6-deoxy-6-(2-pyrimidinethio)-β-cyclodextrin, was synthesized and characterized. Its self-assembly behavior was measured in both solution and the solid state. The crystal structure shows that the pyrimidine group penetrates deeply into the hydrophobic cavity of the adjacent β-cyclodextrin from the second side, and the molecules are stacked along the twofold screw axis to form a head-to-tail helical columnar superstructure. Furthermore, the effective binding constant K and the aggregation number n were calculated to be 354M−1 and 2.1, respectively, by means of 1H NMR spectroscopy titration. The results indicate that the intramolecular/intermolecular interactions are a critical factor in determining the self-assembly behavior.

Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent

The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native β-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (−)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents.

Time-Resolved and Pulse EPR Study of Triplet States of Alkylketones in β-Cyclodextrin

The triplet states of deoxybenzoin (DOB) and benzophenone (BP) molecules in randomly methylated β-cyclodextrin (CD) cavity are studied by time-resolved (TR) and pulse electron paramagnetic resonance (EPR). The observed TR EPR spectrum of DOB in β-CD at 30 K is close to the spectrum measured in polar solvent trifluoroethanol, revealing strong hydration by water molecules. At the same time, TR EPR spectrum of BP in β-CD corresponds to nonpolar surrounding of the CO-group. The electron spin relaxation times T1 and T2 of triplet BP at 30 K measured by pulse EPR are found to be different in β-CD compared to nonpolar toluene glass. The observed increase of T2 by up to a factor of four in β-CD is caused by the lower vibration amplitude of CO-bond of BP due to the confinement in β-CD. The influence of β-CD with covalently attached nitroxide on the triplet states of DOB and BP is principally different: the excited triplet states could not be observed by TR EPR due to the efficient quenching of the excited states by nitroxide.

Adamantane–platinum conjugate hosted in β-cyclodextrin: Enhancing transport and cytotoxicity by noncovalent modification

This work reports the synthesis of a complex of a carboplatin analog having tethered adamantane that is encapsulated in the hydrophobic cavity of β-cyclodextrin (βCD) and its cytotoxic activity towards human neuroblastoma cells (SK-N-SH). We found that this inclusion complex of βCD adamantane carboplatin analog exhibited higher cytotoxicity towards SK-N-SH cells than carboplatin itself, and the inclusion complex exhibited a higher binding to plasmid pBR322 deoxyribonucleic acid (DNA) than carboplatin. Confocal fluorescence images of SK-N-SH cells treated with βCD having an attached fluorescein isothiocyanate (FITC)-tag exhibited fluorescence in the vicinity of the nuclei of the neuroblastoma cells. Direct measurements of the platinum content in SK-N-SH cells using inductively coupled plasma mass spectrometry (ICP-MS) indicated that the uptake rate of carboplatin was about 4 times higher than βCD adamantane carboplatin analog inclusion complex. When compared to carboplatin, we believe that the higher cytotoxicity of inclusion complex towards SK-N-SH cells is due to its higher DNA binding ability as compared to carboplatin, and more efficient delivery to the nucleus of the cell. This work suggests that the advantage of deliberate noncovalent modification with βCD through host-guest chemistry may also be broadly applicable to other anticancer agents as well.

Complex formation of native and hydroxypropylated cyclodextrins with benzoic acid in aqueous solution: Volumetric and 1H NMR study

Novel data on complexation of benzoic acid by parent and hydroxypropylated cyclodextrins were obtained by densimetry and 1H NMR. Formation of 1:1 inclusion complexes was detected in most cases with the exception of hydroxypropyl-γ-cyclodextrin, which is able to form 1:2 complexes. The data demonstrated penetration of carboxylic group of benzoic acid inside macrocyclic cavity, its insertion into β-cyclodextrin cavity being deeper. Binding constants and volumes of transfer were calculated and analyzed in terms of influence of cyclodextrin structure on binding mode and driving forces of interaction as well as on the complex stability.

Thermodynamic characteristics of the formation of α- and β-cyclodextrin complexes with lumichrome, lumazine, and uracil in aqueous solution

Interactions of α- and β-cyclodextrins with lumichrome and its structural fragments, lumazine and uracil, were studied by means of solubility and 1H NMR spectroscopy. α-Cyclodextrin was found to have a weak complexing ability toward the studied compounds. It was established that β-cyclodextrin forms stable complexes with lumichrome and does not complex with lumazine and uracil. It was shown that only the benzene ring of lumichrome penetrates the β-cyclodextrin cavity, leading to a substantial increase in the solubility of lumichrome in water. We concluded that β-cyclodextrin complexation with lumichrome is highly exothermic due to the van der Waals interactions and hydrogen bonding between polar groups of the reagents.

Carotenoids and β-Cyclodextrin Inclusion Complexes: Raman Spectroscopy and Theoretical Investigation

In the present study, the inclusion processes of β-carotene, astaxanthin, lycopene, and norbixin (NOR) into the β-cyclodextrin (β-CD) cavity were investigated by means of Raman spectroscopy and quantum mechanics calculations. The Raman ν(1) band assigned to C═C stretching was sensitive to the host-guest interaction and in general undergoes a blue shift (3-13 cm(-1)) after inclusion takes place, which is the consequence of the localization of single and double bonds. This is supported by the molecular modeling prediction, which inclusion complexes show the ν(1) band blue shifted by 1-8 cm(-1). The calculated complexation energies was small for most of derivatives and was found to be -11.1 kcal mol(-1) for inclusion of AST and +0.27 kcal mol(-1) for NOR. The stability order was qualitatively correlated to topological parameters accounting for the opening angle of the chain. This means that after inclusion the guest molecules assume a slightly more extended conformation, which enhances the host-guest contact, improving the interaction energy. The results discussed here clearly demonstrate the matrix effect on the carotenes' spectroscopic profile and should contribute to fully characterize the raw samples.

What is the effective dielectric constant in a β-cyclodextrin cavity? Insights from Molecular Dynamics simulations and QM/MM calculations

We report a theoretical study on polarization effects induced by the environment on a solute placed inside a β-cyclodextrin macrocycle in aqueous solution. Calculations are carried out for a simple guest molecule p-nitrochlorobenzene using a combined Molecular Dynamics and QM/MM approach. The results have allowed us to derive an effective dielectric constant for the CD-water environment in the range 3–8 that agrees well with several experimental estimations reported in the literature. The investigation emphasizes the fact that the polarization effect is practically the same for the two possible relative orientations of the host–guest complex. For substrates able to form strong specific interactions with either the CD or the water solvent, the medium effects could be different for different orientations, however. In addition, in those cases, specific medium effect would add to the purely dielectric one. This last fact can explain why experimental studies have led to a very large range of values for the effective dielectric constant of β-CDs cavities.

Interaction of artesunate with β-cyclodextrin: Characterization, thermodynamic parameters, molecular modeling, effect of PEG on complexation and antimalarial activity

Inclusion of artesunate in the cavity of β-cyclodextrin (β-CD) as well as its methyl and hydroxypropyl derivatives was investigated experimentally and by molecular modeling studies. The effect of PEG on the inclusion was also studied. A 1:1 stoichiometry was indicated by phase-solubility studies both in the presence and absence of PEG and suggested by the mass spectrometry. The mode of inclusion was supported by 2D NMR and results were further verified by docking studies utilizing Fast Rigid Exhaustive Docking acronym. The thermodynamic parameters were determined for both binary and ternary systems using solution calorimetry and were found to be best for the methyl-β-cyclodextrin (Me-β-CD) system. However, the presence of PEG improves the complexation ability as evident from elevation in the numerical value of the stability constant (K). Solubility and dissolution profile of binary complex is enhanced in the presence of PEG, which is approximately at par with drug Me-β-CD complexes. In vivo studies showed 100% survivability in artesunate–Me-β-CD complexes.

A model for the shuttle motions of puerarin and daidzin inside the cavity of β-cyclodextrin in aqueous acetic acid: insights from molecular dynamics simulations

Acetic acid acts as one component of the mobile phase to influence separation of puerarin from daidzin when using β-cyclodextrin-substituted media. In this work considering an explicit acetic acid solution, host-guest complexes of β-cyclodextrin (β-CD) with puerarin and daidzin were investigated by molecular dynamics simulations. Computational results indicate different shuttle motions of puerarin and daidzin inside the cavity of β-CD. A model detailing the shuttle motion was constructed, and the relationships between shuttle depth and guest rotation angles, hydrogen bonds, and host-guest interaction energies were analyzed. The results can be used to explain the chromatographic retention mechanisms of puerarin and daidzin with β-CD, and to explore the complexity of host-guest interactions involving β-CD.