Denitrosation of N-Nitrososulfonamide as Chemical Probe for Determination of Binding Constants to Cyclodextrins

The influence of β-CD concentration on the acid hydrolysis of N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) has been studied in the presence and absence of different alcohol concentrations. The rate of the denitrosation reaction in bulk water decrease as the β-CD concentration increases due to MNTS complexation in the CD cavity and the reaction taking place exclusively outside the cyclodextrin. Changes in this inhibition due to the presence of β-CD allow us to obtain the binding constants of different alcohols to the cyclodextrin. These binding constants are in very good agreement with those determined in the bibliography by other methods.     

Effect of Cyclodextrins on the Interaction Between BSA and Sodium Dodecyl Benzene Sulfonate

Cyclodextrins offer the potential of modulating protein–surfactant interactions. In our work, the effect of cyclodextrin (CD) on the interaction between bovine serum albumin (BSA) and the anionic surfactant sodium dodecyl benzene sulfonate (SDBS) has been studied by isothermal titration calorimetry (ITC), fluorescence spectra and circular dichroism measurements. The presences of cyclodextrin can slightly hinder the strong interactions between BSA and SDBS by the combination of electrostatic and hydrophobic interactions between BSA and SDBS. Furthermore, the effectiveness of α-CD is lower than that of β-CD, due to the lower association constant between α-CD and surfactant. The presence of both α- and β-CD totally hinders the nonspecific interactions between BSA and SDBS, because the hydrophobic interaction between cyclodextrin and surfactant is stronger than that between BSA and surfactant.     

Host–Guest Complexation of <Emphasis Type="Italic">β</Emphasis>-, <Emphasis Type="Italic">γ</Emphasis>-Cyclodextrin with Alkyl Trimethyl Ammonium Bromides in Aqueous Solution

As a continuation of our previous investigation, interactions between cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and alkyl trimethylammonium bromides in aqueous solutions have been studied with titration calorimetry and ¹H NMR at 298.15 K. The results are discussed in terms of the amphiphilic interaction of CD with surfactants and the iceberg structure formed by water molecules existing around the hydrophobic tail of surfactant molecules. The stoichiometry of the β-CD–surfactant system is 1:1 whereas that of the γ-CD–surfactant system is 1:2. The corresponding formation enthalpy (negative) of the complexes of the two systems decreases with an increase in the number of carbon atoms (n) in hydrophobic chain of surfactant molecule, C _n H_2n+1, whereas the entropy increases with the enlargement of n.     

Cyclodextrins as Enhancers of the Aqueous Solubility of the Anthelmintic Drug Mebendazole: Thermodynamic Considerations

Summary.  Inclusion complexes of mebendazole with α-, β-, and γ-cyclodextrins, hydroxylpropyl-β-cyclodextrin (HP-β-CD), and methyl-β-cyclodextrin (Me-β-CD) were investigated employing the Higuchi and Connors solubility method. The solubility of mebendazole increased as a function of cyclodextrin concentration showing an A_L phase diagram indicating the formation of soluble complexes with 1:1 stoichiometry. The Gibbs free energies of transfer of the drug from aqueous solution to the cavity of cyclodextrin are negative and increase negatively with increasing cyclodextrin concentration. The solubility of mebendazole as well as the stability constant of its complex with Me-β-CD are found to be affected by the pH of the medium. The Me-β-CD cavity was found to have a greater affinity for the unionized mebendazole rather than the protonated one. Effects of methanol and temperature on these interactions were also investigated to gain further knowledge on the mechanism of the inclusion process. It was found that the interaction between the drug and the cyclodextrin is weakened as the medium becomes more apolar and the temperature increases. Moreover, the thermodynamic parameters for the binding were derived from the dependence of the stability constants on the temperature (van’t Hoff analysis). The formation of the inclusion complexes between the drug and β-CD or its derivatives was found to be enthalpy controlled, with |ΔH °| > T|ΔS °|. This suggests that hydrophobic and van der Waals interactions as well as solvent reorganization are the main driving forces. Furthermore, the size of the cavity of cyclodextrins plays an important role in the association process. Permanent address: Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt. E-mail: i.shehatta@uaeu.ac.ae Received November 30, 2001. Accepted (revised) December 27, 2001     

Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest–host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 °C, and with β-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid–base ionization constants (pK _as) for Diclo in the presence and absence of β-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with α-, β-, and HP-β-CD. In contrast, Diclo forms soluble 1:1 Diclo/γ-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/γ-CD, but the 1:1 complex saturates at 5.8 mM γ-CD with a solubility product constant (pK _sp = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: γ-CD > HP-β-CD > β-CD > α-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with γ-CD, where the overall concentration of the latter exceeds 5.8 mM γ-CD. Both ¹H-NMR spectroscopic and molecular mechanical modeling (MM⁺) studies of Diclo/β-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.     

Host–Guest Interactions of Risperidone with Natural and Modified Cyclodextrins: Phase Solubility, Thermodynamics and Molecular Modeling Studies

The solubility of risperidone (Risp) in aqueous buffered cyclodextrin (CD) solution was investigated for α-, β-, γ- and HP-β-CD. The effects of pH, ionic strength and temperature on complex stability were also explored. Neutral Risp tends to form higher order complexes (1:2) with both β- and HP-β-CD, but only 1:1 type complexes with α-, and γ-CD. The tendency of Risp to complex with cyclodextrins is in the order β-CD > HP-β-CD > γ-CD > α-CD. The 1:1 complex formation constant of Risp/HP-β-CD increases with increasing ionic strength in an opposite trend to the inherent solubility (S ₀) of Risp, thus indicating significant hydrophobic effect. The hydrophobic effect contributes to the extent of 72% towards neutral Risp/HP-β-CD complex stability, while specific interactions contribute only 4.7 kJ/mol. Thermodynamic studies showed that 1:1 Risp/HP-β-CD complex formation is driven by a favorable enthalpy change (ΔH ⁰=−31.2 kJ/mol, ΔS ⁰=−7 J/mol.K) while the 1:2 complex is largely driven by entropy changes (ΔH ⁰=−5.0 kJ/mol, ΔS ⁰=42 J/mol.K). Complex stability was found to vary with pH, with a higher formation constant for neutral Risp. Molecular mechanical computations using MM (atomic charges and bond dipole algorithms) and Amber force fields, which were carried out to explore possible sites of interactions between Risp and CDs and to rationalize complex stoichiometry, produced similar results concerning optimal inclusion complex geometries and stoichiometries.     

A study of alkyl radicals in the matrix of polycrystallinen-alkane γ-irradiated at 77 K

The composition of alkyl radicals (AR) formed by γ-radiolysis (T=77 K) of polycrystallinen-alkanes with different lengths of the carbon chain (C(5), C(7), C(10), C(11), and C(18)) and their polymeric analog (polyethylene) was estimated from the ESR spectra. The ESR spectra of the irradiatedn-alkanes are superpositions of the signals from the H₃CC^.HCH₂− and −CH₂C^.HCH₂− radicals, whose HFS constants with α and β protons as well as the equilibrium conformation are independent of the chain length of then-alkane molecule. A dependence of the concentration of the radicals on the chain length ofn-alkane was found. The absence of the −CH₂C^.H₂ radicals that may arise upon H atom elimination from the Me fragments of then-alkane molecules is most likely related to the transfer of excitation energy from the Me group to the neighboring methylene fragment and the transformation of the −CH₂C^.H₂ radicals into H₃CC^.HCH₂− radicals. With account for this, the concentrations of the AR formed were suggested to be proportional to the number of H atoms at the corresponding C atom. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1034–1037, June, 2000.     

Cyclodextrin effect on solvolysis of ortho benzoyl chlorides

A kinetic study was carried out on the solvolysis of ortho benzoyl chlorides in the presence of α-, β- and γ-Cyclodextrin (CD). The solvolysis mechanism of benzoyl chlorides is sensitive to the substituents, and to the solvent in which the reaction takes place. In water, the behaviour exhibited by benzoyl chlorides which have electron-attracting groups, is consistent with an associative mechanism whilst electron-donating substituents induce a dissociative mechanism. The results obtained in the presence of CD show a decrease in the observed rate constant, k _obs, as the CD concentration increases. This behaviour can be explained if these substrates undergo solvolysis through a dissociative path in the presence of α-, β- and γ-CD.     

A new example of reversal of the order of migration of enantiomers, as a function of cyclodextrin concentration and pH, by cyclodextrin-modified capillary zone electrophoresis: enantioseparation of 6,6′-dibromo-1,1′-binaphthyl-2,2′-diol

Enantioseparation of 6,6′-dibromo-1,1′-binaphthyl-2,2′-diol (DBBD) by cyclodextrin-modified capillary zone electrophoresis (CD-CZE) was studied using the three native α, β, and γ cyclodextrins, the three hydroxypropylated cyclodextrins (2-hydroxypropyl-α, β, and γ), heptakis-2,6-di-O-methyl-β-CD (DM-β-CD), and heptakis-2,3,6-tri-O-methyl-β-cyclodextrin (TM-β-CD). First, the acidity constants of DBBD were determined using capillary electrophoresis, before performing enantioseparation. The influence of the concentrations of the studied cyclodextrins on the enantioseparation was explored and the experimental optimal concentrations were determined and compared to the theoretical optimal concentrations. Moreover, the apparent complexation constants between each studied cyclodextrin and the two DBBD enantiomers were evaluated using a non-linear curve fitting method and three linear plotting methods (x-reciprocal, y-reciprocal and double reciprocal). For TM-β-CD, the order of migration of the enantiomers of DBBD reversed as a function of TM-β-CD concentration. The influence of the nature of methylated cyclodextrin derivatives (methyl-β-CD (M-β-CD) and DM-β-CD) was then studied. Inversion of the order of migration of the enantiomers of DBBD was observed for DM-β-CD, whereas the S enantiomer of DBBD always migrated first for M-β-CD.     

Effect of β-cyclodextrin in artificial chaperones assisted foam fractionation of cellulase

Foam fractionation has the potential to be a low-cost protein separation process; however, it may cause protein denaturation during the foaming process. In previous work with cellulase, artificial chaperones were integrated into the foam fractionation process in order to reduce the loss of enzymatic activity. In this study, other factors were introduced to further reduce the loss of cellulase activity: type of cyclodextrin, cyclodextrin concentration, dilution ratio cyclodextrin to the foamate and holding time. α-Cyclodextrin was almost as effective as β-cyclodextrin in refolding the foamed cellulase-Cetyltrimethylammonium bromide mixture. β-Cyclodextrin (6.5 mM) was almost as effective as 13 mM β-cyclodextrin in refolding. The dilution ratio, seven parts foamate and three parts β-cyclodextrin solution, was found to be most effective among the three ratios tested (7∶3, 1∶1, and 3∶7). The activity after refolding at this dilution ratio is around 0.14 unit/mL The refolding time study showed that the refolding process was found to be most effective for the short refolding times (within 1 h).     

Excess enthalpies for n-alkane/ -carotene+n-alkane/AOT/water systems

The experimental data of excess enthalpies for β-carotene/n-alkane+n-alkane/AOT/water systems at 298.15 K are reported. The H_E dependence on AOT (sodium bis(2-ethylhexyl) sulfosuccinate) concentration and hydrocarbon chain length was investigated. The excess enthalpy was measured using the flow microcalorimeter UNIPAN type 600.     

Cavity size effect on ICT-dual emission of p-(N,N-dimethylamino)-2-styrylquinoline: complexation with cyclodextrin derivatives

The effect of cyclodextrin inclusion complex formation on the intramolecular charge transfer (ICT) of the included 4-N,N-dimethylamino-2-strylquinoline (2-StQ-NMe₂) has been studied in detail. 2-StQ-NMe₂ in presence of α-, β-, γ- and HP-α- and Hp-β-CDs predominantly exhibits ICT fluorescence predominantly than the emission from locally excited state, whereas in presence of HP-γ-CD the later is observed. In presence of α-CD, 2:1 complexation of the 2-StQ-NMe₂ is observed in addition to 1:1 complexation. The observed results are explained by the CD cavity size and an active role for the secondary hydroxyl groups present in the wider rim of the CD cavity and also which finds support from absorption, emission, lifetime and molecular modeling studies. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Evaluation of host-guest complex formation between a benzimidazolic derivative and cyclodextrins by UV-VIS spectrophotometry and differential scanning calorimetry

Interactions between a benzimidazolic derivative, omeprazole (OME), beta-cyclodextrin (βCD) and a chemically modified βCD, methyl-beta-cyclodextrin (MβCD) were investigated in aqueous solution by UV-VIS spectroscopy and in solid state by differential scanning calorimetry (DSC). Phase solubility studies were used to evaluate the complexation in aqueous solution. The two solubility diagrams obtained were A_L type, indicating the formation of a drug-cyclodextrin complex with 1:1 stoichiometry. The complex of OME with MβCD showed a higher stability constant (K _S) than those with βCD. Some evidences of inclusion complexation in solid state were obtained from DSC. Only in thermal curves of OME-βCD lyophilized product and in OME-MβCD spray-dried and lyophilized systems the melting point of the drug disappeared completely suggesting the possible formation of an inclusion complex.     

Oxidation of steroidal diols and triols with air/NaH

Abstract  

The unusual air oxidation of steroidal triols and diols in the presence of sodium hydride in THF is described. The initial oxidation product, ketone or aldehyde, frequently undergoes further transformations in the reaction medium. The course of the reaction depends on the stereochemistry of the substrate. For example, oxidation of (20R)-20-hydroxymethyl-6β-methoxy-3α,5α-cyclopregnane-16β,17α-diol with air/NaH afforded 6β-methoxy-23,24,25,26,27-pentanor-3α,5α-cyclofurostane-16α,17α-diol in 60% yield whereas similar reaction of (20R)-20-hydroxymethyl-6β-methoxy-3α,5α-cyclopregnane-16α,17α-diol gave 6β-methoxy-D-homo-16a-oxa-3α,5α-cycloandrostan-16-one in 30% yield. The objective of this preliminary study was to select alcohols susceptible to air/NaH oxidation and to establish the effect of conditions on the course of the reaction.     

A Systematic Quantum Chemistry Study on Cyclodextrins

Summary.  AM1 and PM3 modeling of β-hydroxyethyl ether and α-(1→4)-glucobiose indicated that PM3 is advantageous to AM1 in cyclodextrin (CD) chemistry. The conclusion was supported by direct structure optimization of α- and β-CD with AM1 and PM3, in which AM1 gave badly distorted geometries due to unreasonable hydrogen bonding, whereas PM3 reproduced the crystalline structures rather well. Ab initio calculation was for the first time performed on CD, demonstrating the feasibility of this method for future studies concerning CD chemistry. The results also provided valuable insights into the driving forces in CD molecular recognition. Received January 7, 2000. Accepted (revised) March 22, 2000     

Inclusion Complex of 4-Hydroxycoumarin with Cyclodextrins and Its Characterization in Aqueous Solution

The physicochemical properties of 4-hydroxy-7-methoxy-3-phenyl-2H-chromen-2-one (4HC) and β-cyclodextrins (CDs) inclusion complexes were investigated. The phase solubility profile of 4HC with β-cyclodextrin derivatives was classified as A_L-type. Stability constants for complexes with 1:1 molar ratios were calculated from the phase solubility diagrams and indicate the following trend: DMβCD>HPβCD>βCD. The highest value of the binding constant was for 4HC-DMβCD; the binding association constant (K _a) for this complex was determined at different temperatures and the thermodynamic data indicate that 4HC-DMβCD association is mainly an entropically driven process. ¹H NMR and ROESY were carried out, revealing that 4HC is embedded in the apolar cavity of DMβCD with the 4OH group buried in the cyclodextrin cavity with the phenyl group outside, near the primary rim. These results are in agreement with ORAC_FL values; the decrease in the antioxidant activity of 4HC-DMβCD is explained by the effective protection of the hydroxyl group due to complexation.     

Usefulness of cyclodextrin media for the determination of α-cypermethrin by photochemically induced fluorescence: analytical applications to natural waters

The photochemically induced fluorescence (PIF) spectral properties of α-cypermethrin in organic solvents (hexane, dichloromethane, acetonitrile, ethanol) and in cyclodextrin aqueous solutions (β-CD and 2-hydroxypropyl-β-CD, 2-HP-β-CD) were investigated. The photolysis kinetics of α-cypermethrin were evaluated in the various media. The PIF signal was found to be significantly enhanced in the CD media relative to the organic solvents. The stoichiometry and the formation constants of the α-cypermethrin inclusion complexes formed with the CDs were determined. The analytical performances of the PIF method were improved in the presence of HP-β-CD relative to the other media, and a CD-enhanced PIF analytical method was developed. The limits of detection and limits of quantification ranged, respectively, between 6 and 98 ng/mL and between 24 and 343 ng/mL, depending on the medium. Application to the analysis of tap water and Senegal natural water samples collected close to agricultural areas and spiked with α-cypermethrin yielded satisfactory recoveries going from about 77% to 98%. An interference study of foreign species, including pesticides and inorganic ions likely to be present in natural waters, was also carried out. Figure Photolysis reaction of α-cypermethrin in presence of HP-β-CD     

Comparative Study of the Inclusion Complexation of Pizotifen and Ketotifen with Native and Modified Cyclodextrins

The interaction of two benzocycloheptanes namely, pizotifen (Pizo) and ketotifen (Keto), with cyclodextrins (CDs: α-, β-, γ-, and HP-β-CDs) has been investigated by several techniques including phase solubility, X-ray powder diffractometry, ¹H-nuclear magnetic resonance and molecular mechanical modeling. The effects of CD type, pH, ionic strength and temperature on complex stability were also explored. The complex formation constant (K ₁₁) values for the Pizo/CD system follows the decreasing order β-CD > γ-CD > HP-β-CD > α-CD. However, for the Keto/CD system it follows the decreasing order γ-CD > β-CD > HP-β-CD > α-CD. The tendency of Pizo and Keto to complex with β-CD is driven to the extent of 70% by the hydrophobic effect. Complex formation of Keto and Pizo was substantially driven by entropy (>100 J⋅mol⁻¹⋅K⁻¹) but slightly retarded by enthalpy (3–8 kJ⋅mol⁻¹). ¹H-NMR and MM⁺ studies indicate multimodal inclusion of the methylpiperadine, thiophene and phenyl moieties into the β-CD cavity.     

Reactions of functionalized alkyl halides withN-(β-hydroxyalkyl)-N′-hydroxydiazeneN-oxide salts

Some characteristic features of reactions ofN-(β-hydroxyalkyl)-N′-hydroxydiazeneN-oxide salts with various α- and β-functionalized alkyl halides were established. Some α-and β-functionalizedN-(β-hydroxyalkyl)-N′-alkoxydiazeneN-oxides and e ethylenebis[N-(β-hydroxyalkyl)-N′-oxydiazeneN-oxides] were synthesized for the first time. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 123–129, January, 1999.     

Separation of the enantiomers of four chiral drugs by neutral cyclodextrin-mediated capillary zone electrophoresis

Summary Neutral cyclodextrin (CD)-modified capillary zone electrophoresis (CZE) has been applied to the chiral separation of four basic drugs— clorprenaline, benzhexol, esmolol and terazosin. Selector screening and concentration optimization experiments were performed. The resolution was 3.9 for clorprenaline, 2.3 for benzhexol, 3.1 for esmolol and 1.2 for terazosin when the running electrolyte was 60 mM hydroxypropyl-β-CD, 15 mM heptakis (2,3,6-Tri-O-methyl)-β-CD, 60 mM γ-CD and 60 mM heptakis (2,6-di-O-methyl)-β-CD, respectively, in 50 mM, pH 2.5 sodium phosphate buffer.