Inclusion of Ring A of Cholesterol Inside the β-Cyclodextrin Cavity: Evidence from Oxidation Reactions and Structural Studies

The disposition of cholesterol inside the -cyclodextrin cavity(-CD) was deduced from oxidation of cholesterol secondary alcoholgroups by Ca(OCl)₂ and H₂O₂ in thepyridine–acetic acid system. The amount of cholest-4-ene-3-one formedwas found to be proportional to the concentration of -cyclodextrin,resulting in 56.1% of ketone. The oxidation rate was enhanced by-cyclodextrin and its methyl, polymer and 1 : 1copper(II)–-cyclodextrin derivatives. Detailed investigationsinvolving UV-visible, ¹³C- and ¹H-NMR(T₁, 1D NOE and ROESY) spectroscopic studies were carried out.A binding constant value of 15,385 ± 1500 M^-2 wasobtained for the 2 : 1heptakis-2,6-di-O-methyl--cyclodextrin(DM-CD) : cholesterolcomplex in chloroform from UV studies. Proton and solid state¹³C-CP MAS spectra of the -CD–cholesterol mixtureshowed large magnitude shifts for the protons from the wider end of the-CD cavity as well as those of ring A and ring B of cholesterol. Both1D NOE and ROESY measurements indicated the proximity between ring A andring B protons of cholesterol and the wider end protons of -CD andDM-CD. Besides, analysis of _c,_i and tau;_m from T₁measurements showed not only a lowering of rotational motions but a value of 0.016–0.048 for some of the cholesterol protons, typical of aweak complex. Based on these studies, a probable structure for the 2 : 1complex involving two molecules of -CD/DM-CD was proposed withportions of ring A and ring B being present inside the wider end of the-CD/DM-CD cavity and ring D and the side chain attached atposition 17, projecting into the wider end of the secondCD/DM-CD molecule.     

Effect ofβ-cyclodextrin complexation on the photohaemolitic activity induced by Ketoprofen and Naproxen sensitization

Red blood cell lysis photosensitized by two non-steroidal anti-inflammatory drugs Naproxen (NAP) and Ketoprofen (KPF) was investigated in the presence of -cyclodextrin (-Cyd). The photohaemolysis was inhibited by the addition of -Cyd both for NAP and, to a lesser extent, for KPF. The protective action was found only in a restricted range of concentration of -Cyd. Higher amounts of -Cyd interfered with the resistance of the cell to the osmotic shock induced by the photosensitization process. The complexing action of -Cyd was ascertained through UV-vis absorption spectroscopy, induced circular dichroism and emission spectroscopy.The isolated complexes Naproxen--Cyd (NAP--Cyd) and Ketoprofen--Cyd (KPF--Cyd) were found to protect from the photosensitized membrane damage induced by the two drugs, even if it occurred only in a limited range of concentration. This suggests a valid tool in alleviating thein vitro phototoxic consequences caused by these compounds, even if care has to be taken in therapeutic administration due to the presence of the uncomplexed -Cyd.     

Sodium Dithionite Reduction of 2S,5R-(-)-menthone and R-(+)-pulegone in the Presence of β-Cyclodextrin and Hydroxypropyl-β-cyclodextrin

Menthone on reduction with sodium dithionite,showed a good amount of mentholformation in the water/DMF system, withincreasing -cyclodextrin (-CD)concentration from 47.0% for 0.1 equivalent of-CD to 93.5% for 1 equivalentof -CD. Increasing hydroxypropyl--cyclodextrin(HP-CD) gave higher menthol/neomenthol (M/N) ratiosfrom 2.8 to 3.5. In the case of pulegone,increasing -CD showed an increase in the formationof menthols in thewater/DMF system from 13.3% for 0.1 equivalent of-CD to 78.1% for 1equivalent of -CD with greater proportions ofneomenthol and neoisomenthol.However, HP-CD which showed only marginalenhancement in the formationof menthol from menthone (32.1–41%), exhibiteda greater proportion of mentholformation in the case of pulegone (55.1%).However, the phase-transfer capabilityof HP-CD was not found to be significant.     

Improvement of Solubility and Dissolution of 19-Norprogesterone via Inclusion Complexation

In an effort to modify the solubility and dissolution rate of the contraceptive steroid, 19-norprogesterone in order to improve its bioavailability, the cyclodextrin complexation approach was chosen. In solution, the complex formation with -cyclodextrin (-CD), hydroxyethyl -cyclodextrin (HE--CD) and hydroxypropyl -cyclodextrin (HP--CD) was confirmed by using solubility, UV, IR and ¹H-NMR spectrophotometric techniques. The phase solubility diagrams were categorized as A_L-type. The complexing affinity of the CDs investigated were ranked as follows: -CD > HP--CD > HE--CD. The complexation thermodynamic parameters were obtained from the temperature dependence of the dissociation constants. In the solid state, differential scanning calorimetery (DSC) and optical microscopy methods were utilized to characterize the complexes. Dissolution studies showed that such molecularly encapsulated forms offered a marked improvement in the dissolution rate compared to the parent drug.     

An Investigation of Inclusion Complexes of Cyclodextrins with Phenylurea Herbicides by Photochemically-Induced Fluorescence. Analytical Applications

The effect of -cyclodextrin (-CD) and hydroxypropyl--cyclodextrin (HP--CD) upon the photochemically-induced fluorescence (PIF) properties of four phenylurea herbicides, including linuron, diuron, isoproturon and neburon has been studied. Photochemical conversion of these nonfluorescent herbicides into strongly fluorescent photoproducts was shown to occur in -CD and HP--CD aqueous media. The influence of pH, UV irradiation time and photoproduct stability on the fluorescence intensity was also investigated. In addition, the stoichiometry and formation constants of the complexes formed between herbicides and -cyclodextrin (-CD) or 2-hydroxypropyl--cyclodextrin (HP--CD) were determined. The formation constant values, ranging from 184 ± 40 to 1498 ± 245 M^-1, were calculated by applying the iterative nonlinear regression (NLR) approach to the PIF data. Linear calibrations graphs were established in the interval 1–12 g/mL, for diuron, linuron and neburon. The IUPAC limits of detection ranged between 580 and 700 ng/mL, according to the compound. Application to the analysis of phenylurea herbicides in spiked river water was also described.     

Solubility Study of Nimodipine Inclusion Complexation with α- and β-Cyclodextrin and some Substituted Cyclodextrins

The solubility of nimodipine was measured in aqueous solutions of the following cyclodextrins: -cyclodextrin (-CD), hydroxypropyl--CD (HP--CD), -cyclodextrin (-CD), random substituted methyl--CD (M--CD), three hydroxypropyl--CDs (HP--CD) with mutually different average degree of substitution, and hydroxypropyl--cyclodextrin (HP--CD). From the determined linear solubility diagrams the values of the binding constant K₁₁ of the inclusion complexes of nimodipine with the respective CDs were evaluated. The -CDs efficiently solubilized sparingly soluble nimodipine, the highest value of K₁₁ was found for M--CD (1680 M^-1), followed by -CD (550 M^-1) and HP--CDs, where the higher degree of substitution lowered K₁₁. Only slight solubilization of nimodipine was observed in the solutions of the -CDs and HP--CD.     

Surface Tension and 1H NMR Studies on Inclusion Complexes of β-Cyclodextrin with Sodium Alkyl Sulfonate

The inclusion complexes of -CD with sodium octylsulfonate (C8As), sodium dodecyl sulfonate (C12As), andsodium hexadecyl sulfonate (C16As) in aqueous solutions havebeen studied by surface tension measurement at the air/water interfaceand 1H NMR spectroscopy at 323 K.At fixed concentrations of the surfactants, the surface tensions firstincrease with the increase of -CD concentrations,then they attain a maximum. The surface tension curves of the surfactantsin the presence of -CD are higher than those in the absence of-CD. The values increase with increasing -CD concentrations foreach surfactant. The apparent critical micelle concentrations (CMC) of thesurfactants vary linearly with -CD concentrations.A 1H NMR study shows that the signals of theinner H-3 and H-5 of -CDshift upfield upon addition of the surfactants.The magnitude of the chemicalshift changes (= CD obs)varies as a functionof the concentrations of the surfactants. From therelationships between the chemicalshift changes of H-3 or H-5 inside the -CD cavityand guest/host molar ratios, a 1:1 stoichiometry foreach inclusion complex is assumed. The associationconstants of the inclusion complexes have beendetermined by 1H NMR spectroscopy.     

Reactions of regioisomeric fluoroalkyl-containing β-aminovinyl ketones with hydrazines

Fluoroalkyl -alkyl--aminovinyl ketones react with hydrazine hydrate to give the respective razoles and with phenylhydrazine they form a mixture of pyrazoles and 5 hydroxy-²-pyrazolines. Alkyl(aryl) -fluoroalkyl--aminovinylketones do not react with the hydrazines mentioned above. With 2,4-dinitrophenylhydrazine, both types of fluoroalkyl-containing -aminovinyl ketones give only hydrazones of the corresponding methyl alkyl(aryl) ketones.     

Effects of Modified β-Cyclodextrins on the Hydrolysis Reaction of p-Nitrophenyl α-Methoxyphenylacetate

Effects of -cyclodextrin (-CD) 1and its derivatives 2–7 on the deacylationreaction of p-nitrophenyl (R or S)--methoxyphenylacetatewere studied. The-CD derivatives used were6--D-glucosyl--CD 2, sulfated-CD (7–11 sulfate groups/CD ring) 3,dimethylated -CD 4, carboxymethylated-CD (3.5 carboxymethyl groups/CD ring) 5,2-tri(2-hydroxypropyl)--CD 6, and-CD appended on poly(allylamine) 7. Therate constant (k ^CD) of thesubstrate/-CD complexes and the formationconstants (K) of the complexes were determinedfrom the dependence of the pseudo-first order rateconstants of the deacylation reaction on theconcentration of -CDs. The order ofk ^CD for the R-enantiomer at pH8.0 is 45H₂O3 6 1 2 7, whilethat for the S-enantiomer is 4 5 6H₂O 1 2 3 7: H₂O denotes the rate in theabsence of -CDs. The order of K values is3 7 6 2 1 4 5. This work indicates that, though thesecondary hydroxyl groups of -CD play criticalroles in the deacylation reactions of the esterscomplexed with -CDs, the reactivity of theester/-CD complexes depends highly on thenature of the substituents at the secondary face of-CD. It also suggests that the substratesinserted from the secondary side as well as theprimary side of -CD of poly(allylamine)-bound-CD undergo the reaction by attack of aminogroups on the polymer chain.     

Sulfur heterocycles. 13. Oxidative chlorination of β-thiolactones. A novel synthesis of β-(chlorosulfinyl)alkanoyl chlorides and 1,2-oxathiolan-5-one 2-oxides

Chlorination of -thiolactones with chlorine or sulfuryl chloride in acetic anhydride at a reactant ratio (RR) of 1:2:1 gives -(chlorosulfinyl)alkanoyl chlorides in 75–89% yields. Oxidative chlorination of -thiolactones with RR of 1:3:2 affords -(chlorosulfinyl)alkanoyl chlorides and cyclic sulfinic anhydrides (1,2-oxathiolan-5-one 2-oxides). The optimum RR for the preparation of 1,2-oxathiolan-5-one 2-oxides is 1:2:2. Hydrolysis of -chloro--(chlorosulfinyl)carbonyl chlorides has given novel -chlorinated sulfinocarboxylic acids.For communication 12, see [1].A. N. Nesmeyanov Institute of Heteroorganic Chemistry, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 9, pp. 2153–2158, September, 1992.     

Nitrosation of mefenorex in the presence of cyclodextrins

- and -Cyclodextrin (CD) and heptakis-2,6-di-O-methyl--cyclodextrin (DIMEB) form soluble inclusion compounds with mefenorex (MEF); with -CD a partial inclusion occurs. No solid inclusion compound could be obtained with the four CDs. -, -CD and DIMEB, but not -CD, enhance the nitrosation rate of MEF if the nitrosation assay procedure (NAP test) is applied. During this reaction with - and -CD, solid inclusion compounds of the CDs and nitrosomefenorex (NMEF) precipitate.Part of the Ph.D. thesis of V. Wedelich, Freie Universität Berlin, 1985.     

Binding of vitamin A byβ-cyclodextrin and heptakis(2,6-O-dimethyl)-β-cyclodextrin

Inclusion complexation of all-trans-retinol, retinal and retinoic acid with -cyclodextrin (-CD) and heptakis(2,6-O-dimethyl)--cyclodextrin (DM--CD) were investigated by means of UV-vis spectroscopy. The association constants (K _a) obtained for vitamin A with DM--CD is greater than with -CD. On the other hand, for the same host compoundK _a values of retinol, retinal and retinoic acid are very close to each other.     

Phosphorescence of lyophilized complexes between cyclodextrins andβ-arylpropiophenones

-Arylpropiophenones do not phosphoresce in homogeneous solution as a result of excited state quenching by the -aryl group. In the presence of cyclodextrins the parent substrate, -phenylpropiophenone, shows readily detectable phosphorescence. The complexes show strong phosphorescence after lyophilization to dryness. The phosphorescence intensity of ring-substituted derivatives is strongly dependent upon molecular size and cavity dimensions, suggesting that the -arylpropiophenones can be used to probe these properties.Issued as NRCC-23907     

Isolation of ovine β-lactoglobulin genetic variants by chromatofocusing: Heterogeneity of β-lactoglobulin A

Summary Chromatofocusing was applied to the isolation of ovine -Lactoglubulin (-Lg) genetic variants. Ovine -Lg A and B, which are known to differ only by a single amino-acid substitution, were separated. Moreover, one component differing from A variant in isoelectric point and relative molecular mass has been isolated in samples containing ovine -Lg A. Although elution of -Lgs occurred far from their normal isoelectric points, chromatofocusing is a powerful technique effective for both analytical and preparative scale.     

Complexation of 6-Deoxy-6-(aminoethyl)amino-β-cyclodextrin with Sodium Cholate and Sodium Deoxycholate

In order to study its guest binding and the inclusion phenomena, 6-deoxy-6-(aminoethyl)amino--cyclodextrin (CDN) was synthesised and its binding properties examined. The complexation phenomena of sodium cholate (NaC) and sodium deoxycholate (NaDC) with CDN has been monitored by the NMR method using ¹³C chemical shift data. The method of continuous variation Job's method has been used to determine the stoichiometry of these supramolecular complexes. The Job's plot confirms the 1 : 1 supramolecular complex for NaC: CDN and the 1 : 2 supramolecular complex for NaDC: CDN. The interaction of NaC and NaDC with CDN has been obtained through two-dimensional Rotational Nuclear Overhauser Effect Spectroscopy (ROESY) NMR. Equilibrium constants were also obtained from ¹³C chemical shift data (C-1, C-3 & C-4) at different pH values (7, 9, & 11).     

Effect of Cyclodextrins on the Chemical Stability of ST1435, a Contraceptive Steroid Progestin, in Aqueous Solution

The influence of cyclodextrins (CDs) on the chemical stability of the contraceptive steroid progestin, ST1435, in aqueous solution has been studied using reversed phase high performance liquid chromatography. The effects of CD structure, temperature, and CD concentration on the rate of degradation were investigated. It was found that the drug degraded to different extents following a pseudo-first order reaction mechanism. The presence of the host molecules affected the degradation rate as a result of complexation which might result in protection of the labile moiety of the drug molecule against degradation. Hydroxypropyl--cyclodextrin (HP--CD) and hydroxyethyl--cyclodextrin (HE--CD) retarded the degradation in contrast to -cyclodextrin (-CD) which accelerated the steroid degradation. The stabilizing action of HP--CD is larger than that of HE--CD. The degradation rate increased upon increasing temperature and the Arrhenius equation is valid. Lineweaver-Burk equation analysis indicated that the steroid included inside the CD cavity degraded three times more slowly than did the free ST1435 in solution. This equation further supported the formation of a 1 : 1 inclusion complex between ST1435 and HP--CD with a stability constant of 934.5 M-1 at 65°C.     

Formulation and Preliminary in vivo Testing of Rufloxacin-Cyclodextrin Ophthalmic Solutions

Aim of the present work was to investigate the effect of somecyclodextrins (CDs) on the solubility and ocular bioavailability of rufloxacin base (RUF), with theultimate goal of developing an ophthalmic formulation. Phase solubility studies of RUF inpH 7.4 buffer were carried out in the presence of -cyclodextrin (-CD),hydroxypropyl--cyclodextrin (HP--CD) and -cyclodextrin(-CD). The effect of hydroxypropyl methylcellulose (HPMC) on RUF solubility was evaluated after heating the solutionscontaining HP--CD at 120 °C.A significant enhancement of RUF solubility was achieved by associatingthe drug with CDs, particularly HP--CD. This CD formed with RUF a less stablecomplex than that formed by -CD, but did not suffer the solubility limitations ofthe parent CD, and showed a higher solubilizing capacity than -CD. Addition of 0.25%(w/v) HPMC to solutions containing HP--CD increased the solubilizing effect of this CD,thus allowing reduction of the amount necessary for solubilization of 0.3% (w/v) RUF.Preliminary pharmacokinetic data in rabbits indicated that theocular bioavailability of 0.3% (w/v) RUF solubilized by HP--CD was higher when compared witha 0.3% (w/v) RUF suspension used as reference.     

Enantiomer separations with chromatographic supports based on β-cyclodextrin polymers immobilized on porous silica. Role of the polymer structure in separating ability

Summary Two -cyclodextrin (-CD)-containing polymers have been prepared either by condensation of -CD molecules with a bifunctional reagent or by grafting a -CD derivative on to a linear polymer (polyvinylimidazole). HPLC stationary phases were obtained by adsorption of the -CD polymers on to silica. The ability of these chromatographic supports to resolve racemic mixtures of organic compounds such as amino acid derivatives, phenylhydantoins, barbiturates, and hydroxycoumarin derivatives has been investigated. Results were found to depend on the chemical structure of the -CD polymers     

Structural Studies on Host + Guest Recognition Sensory Systems

Rhodamine B-ethylenediamine--cyclodextrins (RhB--CDen) and rhodamine B--cyclodextrins (RhB--CD) can form inclusive complexes with many guest molecules, a reaction which can be used as a nucleic acid probe. In this paper, the most stable conformations of RhB--CDen and RhB--CD have been determined by fluorescence experiments and analyzed by molecular modeling simulation. The interaction between RhB--CDen and two guest molecules, 1-borneol and cyclohexanol, has also been investigated. The results showed that RhB--CDen has a stronger interaction with 1-borneol than with cyclohexanol. Borneol could push the three aromatic-rings of rhodamine B out of the CD cavity, while the cyclohexanol could not. The interactive sites of host and guest are also presented.     

Complexation of the Non-steroidal Anti-inflammatory Drug Loxoprofen with Modified and Unmodified β-Cyclodextrins

The inclusion complex of the anti-inflammatory drug, loxoprofen, with -cyclodextrin-(CD), sulfated -CD, and glycerol ether -CD was studied by UV-VIS absorption and ¹H-NMR spectroscopy in solution. The inclusion complex of loxoprofen with -CDs was prepared by freeze-drying, and then characterized in the solid state by thermal analysis, X-ray diffraction, FT-IR and FT-Raman spectroscopy, and scanning electron microscopy (SEM). Furthermore, a physical mixture of loxoprofen/-CD (1/1, mol-%) in the solid state was also characterized. The solubility of the loxoprofen increased on addition of -CDs. The solubility enhancement of the loxoprofen with -CDs is in the following order: glycerol ether -CD > sulfated -CD > -CD.