Hydrogel matrices containing single and mixed natural cyclodextrins. Mechanisms of drug release

Hydrogel networks of α, β or γ-cyclodextrin (CD) and mixtures of α/β or β/γ CDs have been obtained using epichlorohydrin (EP) as a crosslinking agent. Discs of the resulting polymers were evaluated as drug carriers for controlled release using the antiinflammatory naproxen (NAP) as a model drug. βCD polymer (βCDP) has shown the highest amount of drug loaded and the lowest one corresponds to the polymer containing αCD, in agreement with the affinities of NAP for the corresponding cyclodextrins.     

Isosteric heats of sorption of 1-naphthol and phenol from aqueous solutions by beta-cyclodextrin polymers

The sorption of phenol and 1-naphthol from aqueous solutions by beta-cyclodextrin polymers has been analyzed using the isosteric heat approach. This has proven to be a useful tool for comparing the interactions between the sorbents and the sorbates. With the purpose of ascertaining the role of the cyclodextrin cavities and the crosslinking network in the sorption process, analogous sucrose polymers have been prepared using the same crosslinking reagents (epichlorohydrin, succinyl chloride, 1,6-hexamethylene diisocyanate, and toluene-2,4-diisocyanate). The two studied sorbates, phenol and 1-naphthol, also show important differences in their affinities for the cyclodextrin cavities and the crosslinking networks.     

Hydrogels of β-cyclodextrin crosslinked by acylated poly(ethylene glycol): Synthesis and properties

Networks of β-cyclodextrin have been prepared by reaction with acylated poly(ethylene glycol) with a molar mass of 600 g/mol. Samples with different β-cyclodextrin/poly(ethylene glycol) ratios: 1/4, 1/6, 1/8 and 1/10 have been prepared. Both components are bonded by ester groups, resulting in a network that can be degraded by hydrolysis in basic and acidic media. The maximum stability of the hydrogels is reached at pH 4. The hydrogel percentage water content depends on β-cyclodextrin content ranging from 82 to 98, and the swelling data obtained for these hydrogels fit well with a second order kinetics. The sorption behavior of these hydrogels has been tested by employing 1-naphthol as model molecule. The sorption capacity is close to other cyclodextrin networks previously reported and depends on the hydrogel composition and the concentration of 1-naphthol.     

Atom accurate structure determination of alprazolam/cyclodextrin inclusion complexes by ROESY and computational approaches

A lot of interest has been seen in computational methods that provide reliable atom accurate structures of different molecular systems. In this article, we describe the complexation of alprazolam (ALP) with three cyclodextrins, i.e., α-, β- and γ-CD. ROESY spectra showed that no complex was formed between ALP and α-CD however, ring A of ALP formed ICs with β- and γ-CD. Therefore, structures of ALP/β-CD and ALP/γ-CD were obtained by a combination of NMR (2D-ROESY) and computational methods by a quantitative ROESY approach. Here we determined the structures of CD ICs by a method recently used in our laboratory and then the structures were obtained independently by DFT (B3LYP functional and def2-TZVP basis set). The structures obtained by both methods were compared with each other. Results demonstrated that our method provides reasonable structures comparable to DFT, and can be used to obtain highly atom accurate structures of CD inclusion complexes. Quantitative ROESY analysis of MM and MD structures consume less time and are cheap as compared to DFT, which is highly CPU demanding and time taking. Negative values of binding energy showed that the process of inclusion was spontaneous and complexes formed were stable. The large negative value of binding energy for ALP/β-CD as compared to ALP/γ-CD showed a higher binding affinity of ALP towards β-CD. FMO studies also revealed the higher HOMO-LOUMO gap for inclusion complexes as compared to pure ALP. Intermolecular H-bonds formed in both the complexes are also one of the forces responsible for inclusion complex formation.     

Inclusional association as studied by the drying dissipative structure. Part 1. Drying patterns of α-, β- and γ-cyclodextrin

Macroscopic and microscopic drying patterns were observed on a cover glass, a watch glass, and a Petri glass dish during the course of dryness of aqueous solutions of α-cyclodextrin (αCD), β-cyclodextrin (βCD), and γ-cyclodextrin (γCD), i.e., cone shape oligomers of polysaccharide. For all CD molecules, two kinds of macroscopic patterns, outside and inner broad rings and spoke lines formed. Multi-broad rings were formed for βCD in the inner region of the main broad ring at the outside edge especially at the high concentrations. Cooperative drying processes of the convection, sedimentation, and solidification were clarified. Microscopic drying patterns showing the formation of rod-like and/or sward-like crystals were observed mainly in the direction along the spoke lines. The microscopic patterns of βCD were similar to those of some of polysaccharides and polynucleotides the authors studied previously. α- and γ-cyclodextrins were slightly hygroscopic, and clear-cut drying patterns were not observed.     

Removal of organic micro-pollutants from water by β-cyclodextrin triazine polymers

β-Cyclodextrin (CD) polymers were synthesized by nucleophilic substitutions between β-CD with cyanuric chloride. Insoluble polymers were obtained. Polymers were characterized by DSC, TGA, FTIR, SS-¹³CNMR. Polymers and activated carbon (AC-Darco) were used to remove model micro-pollutants of bisphenol-A (BPA), 2-naphthol, 2-cholor-biphenyl (PCBNO1), benzene and dibutyl phthalate from water. The results showed that β-CD-triazine polymers showed better performance to adsorb BPA compared with activated carbon; β-CD-triazine polymer showed similar performance to activated carbon on removing benzene from water; however, it showed worse performance for removing 2-naphthol, PCBNO1 and dibutylphthalate by comparison with activated carbon. β-CD-triazine polymers with varying ratio of β-CD to cyanuric chloride were synthesized and their performance on model micro-pollutants were evaluated. Removal efficiency of micro-pollutants from water for β-CD-triazine polymers correlated with their CD concentration except for removing benzene which showed similar performance.     

Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters with silyl nucleophiles

The Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters, which are easily prepared by the acetalization of β,γ-unsaturated α-keto esters, with silyl nucleophiles is presented. By employing trimethylsilyl enolate and allyltrimethylsilane as nucleophiles, the BF₃-promoted reactions of a series of β,γ-unsaturated α,α-dimethoxy esters bearing aromatic and aliphatic substituents proceeded at the γ-position in an SN2′ manner to furnish γ-substituted α,β-unsaturated α-methoxy esters in good yields with high regioselectivity. In contrast, the reaction using trimethylsilyl cyanide predominantly occurred at the α-position, and the reaction of silyl hydride resulted in a mixture of α- and γ-regioisomers in favor of the γ-substitution products.     

Cyclodextrin solubilization of celecoxib: solid and solution state characterization

The low aqueous solubility of celecoxib (CCB) hampers its oral bioavailability and permeation from aqueous environment through biological membranes. The aim of this study was to enhance the aqueous solubility of CCB by complexation with cyclodextrin (CD) in the presence of water-soluble polymer. The effects of different CDs (αCD, βCD, γCD, 2-hydroxypropyl-β-cyclodextrin and randomly methylated β-cyclodextrin (RMβCD)) and mucoadhesive, water-soluble polymers (hydroxypropyl methylcellulose (HPMC), chitosan and hyaluronic acid) were investigated. The phase solubility profiles and CCB/CD complex characteristics were determined. RMβCD exhibited the greatest solubilizing effect of the two CDs tested. However, γCD was also selected for further investigations due to its safety profile. Addition of polymer to the aqueous CD solutions enhanced the CD solubilization. Formation of CCB/RMβCD/HPMC and CCB/γCD/HPMC ternary complexes resulted in 11 and 19-fold enhancement in the apparent complexation efficiency in comparison to their CCB/CD binary complex, respectively. The size of ternary complex aggregates in solution were determined to be from about 250 to about 350 nm. The data obtained from Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction indicated presence of CCB/CD inclusion complexes in the solid state. Proton nuclear magnetic resonance data demonstrated that CCB was partially and totally inserted into the hydrophobic central cavities of RMβCD and γCD.     

Comparison and correlation of in vitro, in vivo and in silico evaluations of alpha, beta and gamma cyclodextrin complexes of curcumin

In the present study investigated the effect of curcumin (CUR) alpha (α), beta (β) and gamma (γ) cyclodextrin (CD) complexes on its solubility and bioavailability. CUR the active principle of turmeric is a natural antioxidant agent with potent anti-inflammatory activity along with chemotherapeutic and chemopreventive properties. Poor solubility and poor oral bioavailability are the main reasons which preclude CUR use in therapy. Extent of complexation was β-CD complex (82 %) > γ-CD (71 %) > α-CD (65 %). Pulverization method resulted in significant enhancement of CUR (0.002 mg/ml) solubility with CUR α-CD complex (0.364 mg/ml) > CUR β-CD complex (0.186 mg/ml) > CUR γ-CD complex (0.068 mg/ml). Gibbs-free energy and in silico molecular docking studies favour formation of α-CD complex > β-CD complex > γ-CD complex. With reference to CUR, relative bioavailability of CUR α-CD, CUR β-CD and CUR γ-CD complexes were 460, 365 and 99 % respectively. CUR–CD complexes exhibited increased bioavailability with an increase in t_½, tmax, Cmax, AUC, Ka, and MRT; and a decrease in Ke, clearance and Vd values. AUC increase was CUR α-CD complex > CUR β-CD complex > CUR γ-CD complex. Significant difference (p < 0.05) was observed between CUR α-CD complex and CUR γ-CD complex by one-way ANOVA and Dunnett’s post hoc test for multiple comparison analysis. Correlation observed between in vitro, in vivo and in silico methods indicates potential of in silico and in vitro methods in CD selection.     

2,4-Dichlorophenol sorption on cyclodextrin polymers

The sorption of β-cyclodextrin polymer (β-CDP) and γ-cyclodextrin polymer (γ-CDP) toward 2,4-dichlorophenol (2,4-DCP) in aqueous solutions was investigated. The influence of sorption conditions including initial 2,4-DCP concentration, contact time and pH on sorption capability were discussed. Their sorption behaviors for 2,4-DCP were conducted and it was found the sorption kinetics followed the Ho and McKay equation and the film diffusion was the rate-determined step. The sorption isotherm can be correlated to Freundlich model and the sorption capacity on β-CDP was much larger than that on γ-CDP. The maximum sorption capacity of 2,4-DCP for β-CDP was measured to be 0.16 mmol/g with the initial concentration at 0.67 mmol/L at 288 K. The CDPs were easily recovered by ethanol as washing solvent and they could be used as a kind of recyclable sorbents.     

Separation of terbutaline enantiomers in capillary electrophoresis with neutral cyclodextrin-type chiral selectors and investigation of the structure of selector-selectand complexes using nuclear magnetic resonance spectroscopy

The major goal of this study was to determine the affinity pattern of the terbutaline (TB) enantiomers toward α-, β-, γ-, and heptakis(2,3-di-O-acetyl)-β-cyclodextrins and using NMR spectroscopy for the understanding of the fine mechanisms of interaction between the cyclodextrins (CD) and TB enantiomers. It was shown once again that CE in combination with NMR spectroscopy represents a sensitive tool to study the affinity patterns and structure of CD complexes with chiral guests. Opposite affinity patterns of TB enantiomers toward native α- and β-CDs were associated with significant differences between the structure of the related complexes in solution. In particular, the complex between TB enantiomers and α-CD was of the external type, whereas an inclusion complex was formed between TB enantiomers and β-CD. One of the possible structures of the complex between TB and heptakis(2,3-di-O-acetyl)-β-CD (HDA-β-CD) was quite similar to that of TB and β-CD, although the chiral recognition pattern and enantioselectivity of TB complexation with these two CDs were very different.     

Parallel kinetic resolution of acyclic γ-amino-α,β-unsaturated esters: application to the asymmetric synthesis of 4-aminopyrrolidin-2-ones

Conjugate addition of a 50:50 pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and lithium (S)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide to a range of racemic acyclic γ-amino-α,β-unsaturated esters (derived from the corresponding α-amino acids) effects their efficient parallel kinetic resolution, allowing the preparation of enantiopure β,γ-diamino esters. The β,γ-diamino ester products of these reactions are readily converted into the corresponding substituted 4-aminopyrrolidin-2-ones via N-debenzylation and cyclization.     

Pd-catalyzed α-arylation of nitriles and esters and γ-arylation of unsaturated nitriles with TMPZnCl·LiCl

Using TMPZnCl·LiCl as a kinetically highly active base, nitriles and esters undergo a Pd-catalyzed α-arylation under mild conditions. Remarkably, in the case of α,β- or β,γ-unsaturated nitriles, a regioselective γ-arylation or a γ-alkenylation is observed.     

Molecular rearrangements—II: The pyrolysis of benzyl-β-naphthyl ether

When purified benzyl-β-naphthyl ether was heated at 260°, in absence of any promotor, the benzyl group migrated to the α-position of the naphthol nucleus. β-Naphthol, toluene, dibenzyl and 9-phenyl-1,2,7,8-dibenzoxanthene also were formed. When quinoline was used as a solvent, the normal rearrangement products were obtained together with 2- and 4-benzylquinolines and 1(2-quinolyl)2-naphthol and its isomeric 1(4-quinolyl)2-naphthol. When phenol and anisole were used as solvents, the rearrangement was accompanied with benzylation of the solvent.     

The synthesis of β-lactams via a one-pot Reformatsky reaction of imines promoted by Zn/Cp2TiCl2 (cat.)

In the presence of Zn/Cp₂TiCl₂ (cat.) α-bromoacetates, γ-bromocrotonates or α-bromomethylacrylates react with imines in one-pot to form β-lactams, 3-vinyl-β-lactams or α-methylene-γ-lactams, respectively, at room temperature without the need for pretreatment of the solvent and Zn.     

Synthesis of fused α-methylene-γ-butyrolactone derivatives through pyridine-induced addition of phenols to dimethyl acetylenedicarboxylate

The reaction between dimethyl acetylenedicarboxylate and various phenols including phenol, 1-naphthol, 2-naphthol, 8-hydroxyquinoline, 1,6-dihydroxynaphthalene, cathechol, hydroquinone and resorcinol in the presence of catalytic amounts of pyridine leads to fused α-methylene-γ-butyrolactone derivatives in good yields.     

Enantiomeric separation of α-phenylethylamine and its analogs by mixed chiral and achiral stationary phase

A mixed stationary phase of modified β-cyclodextrin, 2,6-di-O-butyl-3-O-butyryl-β-cyclodextrin (phase A), and SE-54 (phase B) was used for enantiomeric separation of α-phenylethylami-ne, o,m,p-methyl and o,m,p-methoxy-substituted analogs. The composition of mixed phase was selected by comparison of each calculated amin(= (γm,i+1)/(γm,i))> the relative retention values of the most adjacent peaks, and γm,last, the relative retention values of the last eluting peak at each preselected ratio. Values of γm,i,α calculated by derived equations were in good agreement with the experimental results obtained with two specified mixed phases. All solutes investigated were almost baseline separated at a predicted composition of phase A and phase B in a single run within 18 minutes.     

Cu-Catalyzed Asymmetric Kinetic Boron Conjugate Addition of γ-Substituted α,β-Unsaturated γ-Lactams

Chiral α,β-unsaturated γ-lactams bearing simple γ- substituents are found in biologically active molecules and natural products, however, their synthesis still remains difficult. Herein, we report an efficient kinetic resolution (KR) of γ-substituted α,β-unsaturated γ-lactams via a Cu-catalyzed asymmetric boron conjugate addition, which also leads to the efficient synthesis of chiral β-hydroxy-γ-lactams with β,γ-stereogenic carbon centers. The KR proceeded smoothly with a wide range of γ-alkyl or aryl substituted substrates including those bearing aromatic heterocycles and different N-protected substrates in up to 347 of s value. Their highly versatile transformations, synthetic utility in biologically active molecules, and inhibitory activities against cisplatin-sensitive ovarian cancer cell A2780 have also been demonstrated. Differing from the well-known mechanism involving Cu−B species in Cu-catalyzed boron conjugate additions, our mechanistic studies using density functional theory (DFT) calculations and experiments indicate that a Lewis acid Cu^I-catalyzed mechanism is the likely pathway in the catalytic reaction.     

Hydrogel of β-cyclodextrin-Grafted Polyethyleneimine: pH-Sensitive Release

Novel pH-sensitive hydrogels were prepared by grafting β-cyclodextrin (βCD) to polyethyleneimine (PEI) and cross-linking βCD using epichlorohydrin (EPI). While the molar ratio of βCD to PEI was kept to 1:50, the molar ratio of EPI to βCD was varied so that it was 3/1, 5/1, and 10/1. When the EPI to βCD ratio was higher, the degree of equilibrium swelling and the percentage release were lower, possibly due to a higher cross-linking density. The % release of blue dextran was much less than that of fluorescein isothiocyanate-dextran (FITC-dextran). The electrostatic interaction of blue dextran with the hydrogel is believed to suppress the release of the dye. Among the hydrogels prepared in this work, the hydrogel prepared using the βCD to EPI ratio of 1/5 was the most pH sensitive in terms of the degree of swelling and the degree of FITC-dextran release.     

Complexation of triptolide and its succinate derivative with cyclodextrins: affinity capillary electrophoresis, isothermal titration calorimetry and 1H NMR studies

The complexation of the triptolide PG490 and its succinate derivative PG490-88Na with various cyclodextrins was studied using three complementary techniques: affinity capillary electrophoresis (ACE), isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). The apparent binding constants of the complexes formed between the drugs and 8 CDs (α-CD, β-CD, γ-CD, HP-α-CD, HP-β-CD, HP-γ-CD, CM-β-CD and amino-β-CD) were determined by ACE through linear Scott's plots. The apparent and averaged binding constants of the complexes formed between PG490-88 and β-CD, γ-CD, HP-α-CD, HP-β-CD or HP-γ-CD are contained in the narrow range 135-167 M(-1). For the anionic CM-β-CD and cationic amino-β-CD, these constants are 38 and 278 M(-1), respectively, which is in accordance with electrostatic repulsions or attractions with the succinate moiety. ITC and NMR investigations for the binding constants determinations were performed for 2 CDs allowing high complexation: HP-β-CD and amino-β-CD. The three techniques provided similar results. ITC and NMR, in contrast to ACE, allowed to study the complexes formed between the neutral compound PG490 and neutral cyclodextrins. A more advanced characterization of the PG 490-88Na/amino-β-CD complex, which displays the highest apparent binding constant, was undertaken using NMR spectroscopy. The 1:1 stoichiometry of the complex was established by (1)H NMR 1D and selective 1D TOCSY experiments using the continuous variation method. Moreover, the 1D and 2D ROESY experiments revealed the inclusion of the isopropyl moiety of the triptolide derivative in the hydrophobic CD cavity. Altogether, the data provide strong evidences that the two triptolide compounds can be efficiently complexed with CD.