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PubMedDate not supplied

A novel selenocystine-beta-cyclodextrin conjugate that acts as a glutathione peroxidase mimic.

A novel artificial glutathione peroxidase mimic consisting of a selenocystine-di-beta-cyclodextrin conjugate (selenium-bridged-6, 6'-amino-selenocystine-6,6'-deoxy-di-beta-cyclodextrin), in which selenocystine is bound to the primary side of beta-cyclodextrin through the two amino nitrogen groups of selenocystine, was synthesized. The glutathione peroxidase activities of the mimic-catalyzed reduction of H(2)O(2), tert-butylhydroperoxide, and cumene hydroperoxide by glutathione are 4.1, 2.11, and 5.82 units/micromol, respectively. The first activity was 82 and 4.2 times as much as that of selenocysteine and ebselen, respectively. Studies on the effect of substrate binding on the glutathione peroxidase activity suggest that it is important to consider substrate binding in designing glutathione peroxidase mimics. The detailed steady-state kinetic studies showed that the mimic-catalyzed reduction of H(2)O(2) by glutathione followed a ping-pong mechanism, which was similar to that of the native glutathione peroxidase.

Binding Sites↗
PubMedDate not supplied

Synthesis of linear, beta-cyclodextrin-based polymers and their camptothecin conjugates.

6(A),6(D)-Bis-(2-amino-2-carboxylethylthio)-6(A),6(D)-dideoxy-beta-cyclodextrin 1, a diamino acid derivative of beta-cyclodextrin, is synthesized and condensed with difunctionalized PEG comonomers to give linear, high molecular weight (M(w) over 50 kDa) beta-cyclodextrin-based polymers (2-4) with pendant functionality (carboxylate). 2-4 are all highly soluble in aqueous solutions (over 200 mg/mL). 20-O-trifluoroglycinylcamptothecin, 5a, and 20-O-trifluoroglycinylglycinylglycinylcamptothecin, 5b, are synthesized and conjugated to 2 to give polymer-camptothecin (CPT) prodrugs. The solubility of CPT is increased by more than three orders of magnitude when it is conjugated to 2. The rates of CPT release from the conjugates HGGG6 (high molecular weight polymer (M(w) 97 kDa), glyglygly linker and 6 wt % CPT loading) and HG6 (high MW polymer (M(w) 97 kDa), gly linker and 6 wt % CPT loading) in either mouse or human plasma are dramatically accelerated over the rates of pure hydrolysis at pH = 7.4, indicating the presence of enzymatic cleavage as a rate-determining step at this pH in the release of the CPT. The pH of aqueous solution has a large effect on hydrolysis rate of CPT from HGGG6 and HG6; the lower the pH, the slower the rate in the range at 4.1 <or= pH <or= 13.1. The IC(50)'s of polymer 2e, CPT, and the CPT conjugates HG6 and HGGG6 are found to be cell-line dependent with LS174T, HT29, A2780, and PC3 cells using in vitro MTT assays. The parent polymer 2e has very low toxicity to all cultured cells tested.

Animals↗
PubMed1995

Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor.

To investigate the effect of cholesterol on the oxytocin receptor function in myometrial membranes, we developed a new method to alter the membrane cholesterol content. Using a methyl-substituted beta-cyclodextrin, we were able to selectively deplete the myometrial plasma membrane of cholesterol. Vice versa, incubating cholesterol-depleted membranes with a preformed soluble cholesterol-methyl-beta-cyclodextrin complex restored the cholesterol content of the plasma membrane. Binding experiments showed that, with the removal of cholesterol from the membrane, the dissociation constant for [3H]oxytocin is enhanced 87-fold (from Kd = 1.5 nM to Kd = 131 nM), therefore shifting the oxytocin receptor from high to low affinity. Increasing the cholesterol content of the cholesterol-depleted membrane again restored the high-affinity binding (Kd = 1.2 nM). The presence of 0.1 mM GTP gamma S did not significantly change the number of high-affinity binding sites for [3H]oxytocin in native plasma membranes, in membranes depleted of cholesterol, and in plasma membranes with restored cholesterol content. The number of high-affinity binding sites for the oxytocin antagonist [3H]PrOTA was dependent in the same way on the cholesterol content as for [3H]oxytocin. Substitution of the membrane cholesterol with other steroids showed a strong dependence of the oxytocin receptor function on the structure of the cholesterol molecule. The detergent-solubilized oxytocin receptor was not saturable with [3H]oxytocin even at concentrations up to 10(-6) M of radioligand. Addition of the cholesterol-methyl-beta-cyclodextrin complex to the detergent-solubilized oxytocin receptor induced a saturation of the solubilized binding sites (Bmax = 0.98 pmol/mg) for oxytocin (Kd = 16 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Calorimetric measurement of phospholipid interaction with methyl-beta-cyclodextrin.

Cyclodextrins are able to bind hydrophobic molecules in their interior cavity and as such have received a great deal of attention as carriers of cholesterol, lipophilic drugs, and other sparingly soluble compounds. Despite the importance of these biochemical applications, relatively little is known about the interactions of cyclodextrins with phospholipid membranes. Here we characterize the binding of randomly methylated beta-cyclodextrin (m beta CD) to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) using right-angle light scattering and isothermal titration calorimetry. Existing models of lipophile-membrane interactions are inadequate to describe the observed binding; we introduce a modified chemical reaction model in which the chemical activity of the phospholipid is independent of its concentration. We find that an average of four m beta CD molecules bind to each POPC molecule with an enthalpy of reaction of 46 kJ mol(-1) and an equilibrium constant of 90 M(-3). These results are consistent with earlier qualitative observations and suggest that disruption of phospholipid membranes may be minimized if the concentration of m beta CD is kept below about 15 mM.

Binding Sites↗
PubMed2001

Competitive binding of aroma compounds by beta-cyclodextrin.

Retention of six aroma compounds has been studied after dehydration of ternary mixtures of aroma water and beta-cyclodextrin. A maximal retention of a mole of aroma per mole of beta-cyclodextrin has been observed for five of the aroma compounds, whereas retention of benzyl alcohol can be twice as high. Retention of a mixture of aroma compounds has also been studied. It has been noted that when volatile compounds compete for the same binding sites on beta-cyclodextrin, ethyl hexanoate, 2-methylbutyric acid, and benzyl alcohol are, respectively, better retained than ethyl propionate, hexanoic acid, and hexanol. Preferential retention observed with esters can be simply explained by their difference of physicochemical properties, but for the acids and alcohols a study at the molecular scale has been necessary. The better retention of 2-methylbutyric acid can be explained by differences in the nature of interaction between the acids and their carrier. At least selectivity of retention noted for the alcohol could be due to a difference in the location of the guest and also a difference in the number of aroma molecules that can be bound per polysaccharide molecule.

Alcohols↗
PubMed2002

Enantioseparation of vinclozolin by gamma-cyclodextrin-modified micellar electrokinetic chromatography.

Cyclodextrin-modified micellar electrokinetic chromatography was applied to the enantioseparation of vinclozolin, which has been used as a fungicide and has an anti-androgenic activity, using gamma-cyclodextrin together with sodium dodecyl sulfate. Factors affecting the chiral resolution and migration time of vinclozolin were studied. The optimum running conditions were found to be 20 mM phosphate-5 mM borate buffer (pH 8.5) containing 50 mM gamma-cyclodextrin and 100 mM sodium dodecyl sulfate with an effective voltage of 20 kV at 20 degrees C using direct detection at 203 nm. Under these conditions, the resolution (Rs) of racemic vinclozolin was approximately 2.1. The sample was concentrated by solid-phase extraction and was fractionated by HPLC. The peak area ratio of (+)- and (-)-vinclozolins in wine was found to be 2:3, namely, not racemic, suggesting that degradation rates were different between (+)- and (-)-vinclozolins. The anti-androgenic activities of (+)- and (-)-vinclozolins on dihydrotestosterone-induced transcription were also investigated. The anti-androgenic activity of (+)-vinclozolin tended to be stronger than that of (-)-vinclozolin, suggesting the possibility that vinclozolin can act as an enantioselective anti-androgen.

Chromatography, High Pressure Liquid↗
PubMed2003

Complexation of several fungicides with beta-cyclodextrin: determination of the association constants and isolation of the solid complexes.

The formation of inclusion complexes with beta-cyclodextrin was studied for several popular fungicides of different types: prochloraz, 2-phenylphenol, thiophanate methyl, 8-hydroxyquinoline, and benalaxyl. Phase solubility diagrams showed that in all cases complexation takes place, leading to an important increase of water solubility in prochloraz and benalaxyl. Equilibrium association constants could be determined from the phase solubility data and from NMR titrations in the case of 2-phenylphenol. Because of the low solubility of the complex formed between 8-hydroxyquinoline and beta-cyclodextrin, the corresponding association constant could not be determined. The solid complexes of fungicide-cyclodextrin were prepared and isolated by different methods. The isolation of real complexes and not physical mixtures was confirmed in the cases of prochloraz, 2-phenylphenol, and benalaxyl by differential scanning calorimetry.

Alanine↗
PubMed1999

Encapsulation of lemon oil by paste method using beta-cyclodextrin: encapsulation efficiency and profile of oil volatiles.

Microencapsulation of lemon oil was undertaken by kneading with beta-cyclodextrin, at a beta-cyclodextrin to lemon oil ratio of 88:12 (w/w). The resulting paste samples of the complex were vacuum- or spray-dried. Ten selected lemon oil flavor volatiles (alpha-pinene, sabinene, beta-pinene, beta-myrcene, limonene, gamma-terpinene, terpinolene, linalool, neral, and geranial) in the complex were analyzed periodically after 1, 2, 5, 10, 15, 20, and 30 min of kneading time. The results indicated that the levels of these volatiles were not significantly different (P > 0.05) irrespective of mixing time or type of the drying (vacuum- or spray-drying) used. An optimum mixing time was found to be 15 min, at which time the maximum encapsulation of lemon oil (97.7 mg/g of beta-cyclodextrin) was obtained in the complex powder.

Chromatography, Gas↗
PubMed2004

Binding ability and assembly behavior of beta-cyclodextrin complexes with 2,2'-dipyridine and 4,4'-dipyridine.

Two channel-type supramolecular aggregations 1 and 2 were prepared by the inclusion complex of beta-cyclodextrin with 2,2'-dipyridine and 4,4'-dipyridine, respectively, and their binding ability and assembly behavior were investigated comprehensively by X-ray crystallography, (1)H NMR, circular dichroism spectra, and microcalorimetric titration in solution and the solid state. The obtained results revealed that the hydrogen bonds and pi-pi stacking interactions are crucial factors for the formation of the molecular aggregations containing beta-cyclodextrin and dipyridines. The disparity of nitrogen atom position in dipyridines leads not only to the distinct crystal system and space group, i.e., monoclinic system (C2) for 1 and triclinic system (P-1) for 2, but also different binding modes and thermodynamical parameters upon complexation of 2,2'-dipyridine and 4,4'-dipyridine with beta-cyclodextrin in aqueous solution.

2,2'-Dipyridyl↗
PubMed1997

Binding of substituted acetic acids to alpha-cyclodextrin in aqueous solution.

Complex binding constants of 23 aliphatic acids with alpha-cyclodextrin in aqueous solution were measured by potentiometry, solubility, or competitive spectrophotometry at 25 degrees C. All systems formed 1:1 acid:cyclodextrin complexes, and some of them also formed 1:2 complexes. The conjugate acids formed stronger complexes than did the conjugate bases (except for glycine). Empirical correlations of complex stabilities are shown with partition coefficients, surface areas, molar refraction, and other descriptors. Complex stability appears to result from the hydrophobic effect, the dispersion interaction, and interaction of the carboxylic acid group with the cyclodextrin.

Acetates↗
PubMed2001

Unique fluorescence behavior of rhodamine B upon inclusion complexation with novel bis(beta-cyclodextrin-6-yl) 2,2'-bipyridine-4,4'-dicarboxylate.

Newly synthesized bis(beta-cyclodextrin-6-yl) 2,2'-bipyridine-4,4'-dicarboxylate was found to induce an unusual fluorescence enhancement of Rhodamine B (RhB) upon complexation. This effect is attributable to the equilibium shift of RhB to the highly fluorescent carboxylate ion form, which is induced by the cooperative binding by two appropriately preorganized cyclodextrin units in the bis(beta-cyclodextrin). This sandwich complexation behavior was investigated by means of the fluorescence and 2D NMR spectroscopy.

Cyclodextrins↗
PubMed2001

Stabilizing and solubilizing effects of sulfobutyl ether beta-cyclodextrin on prostaglandin E1 analogue.

PURPOSE: Parent cyclodextrins are known to accelerate the degradations such as dehydration and isomerization of E-type prostaglandins in neutral and alkaline solutions. The objective of this study was to attempt the stabilization and solubilization of E1-type prostaglandin analogue in aqueous solution by biocompatible cyclodextrin derivatives. METHODS: The interaction of an E1-type prostaglandin, methyl 7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-4-(m-methoxymethylphenyl)1-butenyl]-5-oxocyclopentyl]-5-thiaheptanoate (MEester) with cyclodextrins (CyDs) was studied by spectroscopies and the solubility method. The degradation of MEester was monitored by high-performance liquid chromatography. RESULTS: 1H-nuclear magnetic resonance spectroscopic studies indicated that MEester forms 1:1 inclusion complexes with alpha-, beta-, and gamma-CyDs in solutions, where alpha-CyD interacts with the a-side chain containing methyl ester moiety of the drug, whereas beta- and gamma-CyDs preferentially include around the five-membered ring and both side chains of the drug. Parent alpha-CyD and hydrophilic derivatives, such as 2-hydoxypropyl-alpha- and -beta-CyDs, sulfobutyl ether beta-CyD (SBE-beta-CyD) and maltosyl beta-CyD showed higher solubilizing abilities against MEester over parent beta- and gamma-CyDs. SBE-beta-CyD and 2,6-dimethyl-beta-CyD (DM-beta-CyD) significantly decelerated the degradation of MEester, particularly the base-catalyzed dehydration, in neutral and alkaline solutions, whereas other CyDs accelerated the degradation. The acid-catalyzed degradation of MEester (pH < 3) was decelerated by the addition of CyDs, especially alpha-CyD. CONCLUSIONS: SBE-beta-CyD with low hemolytic activity and low toxicity is useful as a pharmaceutical carrier for the preparation of injectable MEester, because of its higher stabilizing and solubilizing effects on MEester. Furthermore, SBE-beta-CyD can be useful as a stabilizing agent for drugs, that are subject to base-catalyzed degradations, probably because of the electric repulsion between anionic charges of the sulfobutyl moiety and catalytic anionic species such as hydroxide ion.

Alprostadil↗
PubMed1992

1H-nuclear magnetic resonance (NMR) studies on the inclusion complex of prostaglandin E1 (PGE1) with alpha-cyclodextrin.

Prostaglandin E1 is currently marketed as a freeze-dried injectable inclusion complex with alpha-cyclodextrin for the treatment of peripheral arterial diseases. alpha-Cyclodextrin is used as a stabilizing agent and to improve the dissolution characteristics of prostaglandin E1. Upon dilution with the infusion medium, the inclusion complex dissociates almost completely as shown by NMR chemical shift measurements of the complexed and uncomplexed prostaglandin E1. Nuclear Overhauser effect (NOE) measurements of the interacting atoms of alpha-cyclodextrin and prostaglandin E1 provide insight into the structure of the complex.

Alprostadil↗
PubMed1996

Delivery of nasal powders of beta-cyclodextrin by insufflation.

PURPOSE: Delivery of nasal powders of granulated beta-cyclodextrin by insufflation was studied in order to find the relationship between powder properties and delivery behavior. METHODS: Three nasal powder formulations, prepared by granulating beta-cyclodextrin with different binders, were delivered from a powder insufflation device, in which the dose to be emitted was loaded in a gelatin capsule. The delivery sequence of powder was recorded and characterized using an image analysis program. RESULTS: Particle size was the main parameter affecting nasal powder delivery, both as to the amount of dose sprayed and the aspect of cloud produced. Between 50-150 mu m of particle size a substantial change in delivery behavior of powders was observed. Powder of around 100 mu m in size showed useful insufflation characteristics for nasal delivery. Bioavailability of nasal formulations of progesterone/beta-cyclodextrin powders was discussed in term of delivery behavior. CONCLUSIONS: The formulation approaches for improving nasal delivery of powders require the use of size optimized carriers. Insufflation of powders over 50 mu m can favour the particle deposition by impaction, whereas for powders below 50 mu m, deposition by sedimentation is moved. beta-cyclodextrin is a suitable carrier for achieving high systemic availability following nasal administration of powder formulations.

Administration, Intranasal↗
PubMed1993

Preparation of heptakis(2,6-di-O-ethyl)-beta-cyclodextrin and its nuclear magnetic resonance spectroscopic characterization.

Heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (DE-beta-CyD) was prepared and its 1H and 13C nuclear magnetic resonance (NMR) signals in DMSO-d6 were unequivocally assigned by two-dimensional COSY and ROESY. The results on 1H coupling constants indicated that all ethylated glucose units are in a 4C1 chair conformation. The average spin-lattice relaxation times (T1) of ring carbons of DE-beta-CyD were only slightly shorter, and their standard deviations from the mean T1 value were larger, than those of beta-cyclodextrin (beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), suggesting the presence of slightly irregular internal motion in the ethylated glucose units. The temperature dependence of chemical shift of DE-beta-CyD in DMSO-d6 suggested that the C3 hydroxyl protons may participate as proton donor in the intramolecular hydrogen bond to the C2 ethoxyl groups of neighboring glucose, and the intramolecular hydrogen bond of DE- and DM-beta-CyDs is much stronger than that of beta-CyD, suggesting the stable macrocyclic ring structure of DE-beta-CyD.

Chemical Phenomena↗
PubMed2003

Diazacoronand linked beta-cyclodextrin dimer complexes of Brilliant Yellow tetraanion and their sodium(I) analogues.

Complexation of the Brilliant Yellow tetraanion, 3(4-), by two new diazacoronand linked beta-cyclodextrin (beta CD) dimers 4,13-bis(2-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl- and 4,13-bis(8-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl)-4,13- diaza-1,7,10-trioxacyclopentadecane, 1 and 2, respectively, has been studied in aqueous solution. UV-visible spectrophotometric studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NEt4ClO4) yielded complexation constants for the complexes 1 x 3(4-) and 2 x 3(4-), K1 = (1.08 +/- 0.01) x 10(5) and (6.21 +/- 0.08) x 10(3) dm3 mol-1, respectively. Similar studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NaClO4) yielded K3 = (4.63 +/- 0.09) x 10(5) and (3.38 +/- 0.05) x 10(4) dm3 mol-1 for the complexation of 3(4-) by Na+ x 1 and Na+ x 2 to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-), respectively. Potentiometric studies of the complexation of Na+ by 1 and 2 by the diazacoronand component of the linkers to give Na+ x 1 and Na+ x 2 yielded K2 = (2.00 +/- 0.05) x 10(3) and (1.8 +/- 0.05) x 10(3) dm3 mol-1, respectively, at 298.2 K and I = 0.10 mol dm-3(NEt4ClO4). For complexation of Na+ by 1 x 3(4-) and 2 x 3(4-) to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-) K2K3/K1 = K4 = 8.6 x 10(2) and 9.8 x 10(3) dm3 mol-1, respectively. The pKaS of 1H4(4+) are 7.63 +/- 0.01, 6.84 +/- 0.02, 5.51 +/- 0.04 and 4.98 +/- 0.03, and those of 2H4(4+) are 8.67 +/- 0.02, 8.11 +/- 0.02, 6.06 +/- 0.02 and 5.14 +/- 0.05. The larger magnitude of K1 for 1 by comparison with K1 for 2 is attributed to the octamethylene linkers of 2 competing with 3(4-) for occupancy of the annuli of the beta CD entities while the competitive ability of the dimethylene linkers of 1 is less. A similar argument applies to the relative magnitudes of K3 for Na+ x 1 and Na+ x 2. Increased electrostatic attraction probably accounts for K3 > K1 for Na+ x 1 x 3(4-) and 1 x 3(4-) and for Na+ x 2 x 3(4-) and 2 x 3(4-). The lesser magnitudes of K2 and K4 for Na+ x 1 and Na+ x 1 x 3(4-) compared with those for Na+ x 2 and Na+ x 2 x 3(4-) are attributed to the octamethylene linkers of 2 producing a more hydrophobic environment for the diazacoronand than that produced by the dimethylene linkers of 1. 1H NMR spectroscopic studies and the syntheses of 1 and 2 are described.

Anions↗
PubMed2003

A diffuse reflectance comparative study of benzil inclusion within microcrystalline cellulose and beta-cyclodextrin.

Diffuse reflectance and laser-induced techniques were used to study photochemical and photophysical processes of benzil adsorbed on two solid powdered supports, microcrystalline cellulose and [small beta]-cyclodextrin. In both substrates, a distribution of ground-state benzil conformers exists, largely dominated by skew conformations where the carbonyl groups are twisted one to the other. Room temperature phosphorescence was observed in air-equilibrated samples in both cases. The decay times vary greatly and the largest lifetime was obtained for benzil/[small beta]-cyclodextrin, showing that this host's cavity accommodates benzil well, enhancing its room temperature phosphorescence. Triplet-triplet absorption of benzil entrapped in cellulose was detected and benzil ketyl radical formation also occurred. With benzil included into [small beta]-cyclodextrin, and following laser excitation, benzoyl radicals were detected on the millisecond timescale. Product analysis and identification of laser-irradiated benzil samples in the two hosts clearly showed that the main degradation photoproducts were benzoic acid and benzaldehyde. The main differences were a larger benzoic acid/benzaldehyde ratio in the case of cellulose and the formation of benzyl alcohol in this support.

Adsorption↗
PubMed2004

Bis(phenylthienyl)ethene-tethered beta-cyclodextrin dimers as photoswitchable hosts.

Two beta-cyclodextrin dimers tethered by photoswitchable bis(phenylthienyl)ethene moieties were synthesized as potentially tunable receptor molecules. The cyclodextrin cavities of these dimers were linked via their secondary sides, with the photochromic bis(phenylthienyl)ethene unit either directly connected to the secondary rim (7) or via propyl spacers (10). By irradiation with light the dimers were reversibly switched between a relatively flexible (open) form and a rigid (closed) form. The photostationary states for both dimers consisted of 92% of the open and 8% of the closed form, enabling the nearly complete conversion between the two forms. The binding properties of the open and closed forms of dimers 7 and 10 were assessed by complexation studies with meso-tetrakis(4-sulfonatophenyl)porphyrin (TSPP) using isothermal titration calorimetry. For the rigidly tethered dimer 7, a factor 8 difference in binding affinity between the open and closed form of the dimer was found. This difference in binding affinity reflects the difference in enthalpy of binding for the two dimers, indicating that the beta-cyclodextrin cavities of the closed dimer 7b are spaced too far apart from each other by the rigid closed bis(phenylthienyl)ethene tether to cooperatively bind TSPP. The difference in binding affinity was sufficient to enable the phototriggered release of TSPP from dimer. The thermodynamic parameters obtained for dimer 10 suggested that the closed tether substantially contributes to the binding of TSPP. The open and closed form of dimer 10 bound TSPP with similar association constants, although the enthalpy of binding for the complexation of TSPP by the closed form of dimer 10 was more favorable than that found for the open form of the dimer.

Calorimetry↗