Mutual induced fit in cyclodextrin-rocuronium complexes

The binding of rocuronium bromide to 6-perdeoxy-6-per(4-carboxyphenyl)thio-gamma-cyclodextrin sodium salt, displays biphasic behaviour characteristic of the formation of a binary and 2 : 1 ternary guest-host complex in aqueous solution. Thermodynamic and structural data on this sequential complexation process can be rationalised within a single model involving switching of the conformational equilibria of both the rocuronium bromide and cyclodextrin molecules. Isothermal titration calorimetry (ITC), NMR and fluorescence experiments in solution, together with X-ray crystallography and molecular modelling, suggest that in order to induce encapsulation both rocuronium bromide and the modified cyclodextrin undergo conformational changes. Ring A of rocuronium bromide 'switches' from the more sterically encumbered chair to the sterically less demanding twist-boat, whilst the modified cyclodextrin "opens" its cavity to allow the steroid to enter. The recognition and mutual induced fit between cyclodextrin and steroid represents a classic example of dynamic host-guest chemistry.     

环糊精及其衍生物包合作用的理论研究进展

简要介绍了环糊精及其衍生物包合作用的理论研究进展,重点评述理论化学方法在环糊精的理化性质、环糊精包合客体分子的主要弱相互作用中的重要应用及其主要结果,并介绍了目前新的最常出现的部分理论研究方法.     

Crown ethers derived from cyclodextrin: Interaction with triphenylmethane derivatives

Periodate oxidation followed by borohydride reduction of beta cyclodextrin results in crown ether type derivatives. The polyaldehyde obtained by periodate oxidation has been reduced to polyalcohol and converted to a permethylated derivative. These macrorings are much more flexible than beta cyclodextrin itself.The interaction of beta cyclodextrin (-CD), methylated beta cyclodextrin (DIMEB), polyalcohol and permethylated crown ethers derived from beta cyclodextrin with two triphenylmethane, derivatives and their triphenyltin analogues has been studied. On the basis of the changes in the UV spectra and the solubility enhancement it can be concluded that cyclodextrins (-CD and DIMEB) form complexes only with the triphenylmethane, derivatives. On the other hand the crown ethers prepared from -CD give complexes only with the triphenyltin derivatives.     

Influence of substituent position and cavity size of the regioisomers of monocarboxymethyl‐α‐, β‐, and γ‐cyclodextrins on the apparent stability constants of their complexes with both enantiomers of Tröger's base

Enantiomers of Tröger's base were separated by capillary electrophoresis using 2^I‐O‐, 3^I‐O‐, and 6^I‐O‐carboxymethyl‐α‐, β‐, and γ‐cyclodextrin and native α‐, β‐, and γ‐cyclodextrin as chiral additives at 0–12 mmol/L for β‐cyclodextrin and its derivatives and 0–50 mmol/L for α‐ and γ‐cyclodextrins and their derivatives in a background electrolyte composed of sodium phosphate buffer at 20 mmol/L concentration and pH 2.5. Apparent stability constants of all cyclodextrin–Tröger's base complexes were calculated based on capillary electrophoresis data. The obtained results showed that the position of the carboxymethyl group as well as the cavity size of the individual cyclodextrin significantly influences the apparent stability constants of cyclodextrin–Tröger's base complexes.     

The structure and properties of functionalized cyclodextrins and complex compounds based on them

Russian Chemical Bulletin - This review presents data on advanced research on functionalized cyclodextrins. In particular, metal complexes of cyclodextrin derivatives and their possible...     

Cyclodextrin knowledgebase a web-based service managing CD-ligand complexation data

Cyclodextrins are cyclic oligosaccharides that are able to form water-soluble inclusion complexes with small molecules. Because of their complexing ability, they are widely applied in food, pharmaceutical and chemical industries. In this paper we describe the development of a free web-service, Cyclodextrin KnowledgeBase: (http://www.cyclodextrin.net). The database contains four modules: the Publication, Interaction, Chirality and Analysis Modules. In the Publication Module, almost 50,000 publication details are collected that can be retrieved by text search. In the Interaction and Chirality Modules relevant literature data on cyclodextrin complexation and chiral recognition are collected that can be retrieved by both text and structural searches. Moreover, in the Analysis Module, the geometries of small molecule-cyclodextrin complexes can be predicted using molecular docking tools in order to explore the structures and interaction energies of the inclusion complexes. Complex geometry prediction is made possible by the built-in database of 95 cyclodextrin derivatives, where the 3D structures as well as the partial charges are calculated and stored for further utilization. The use of the database is demonstrated by several examples.     

Inclusion complexes of cyclodextrins with biradicals linked by a polyether chain--an EPR study

Complexation of beta-cyclodextrin with flexible nitroxide biradicals linked by a polyethylene glycol chain was monitored by EPR spectroscopy. The EPR spectra of the uncomplexed biradicals show an exchange interaction due to the flexibility of the polyethylene glycol chain. Complexation with cyclodextrin leads to the disappearance of the exchange interaction in the EPR spectra. The complexation can be reversed by the addition of competing guests (e.g., adamantane derivatives). At high concentration, the inclusion complexes precipitate, and differential scanning calorimetry (DSC) of the precipitates proved the formation of complexes. Elemental analysis data revealed that the complexes contain several cyclodextrin units per biradical but that the composition was not stoichiometric.     

Characterization of complexes between phenethylamine enantiomers and β‐cyclodextrin derivatives by capillary electrophoresis—Determination of binding constants and complex mobilities

To optimize chiral separation conditions and to improve the knowledge of enantioseparation, it is important to know the binding constants K between analytes and cyclodextrins and the electrophoretic mobilities of the temporarily formed analyte‐cyclodextrin‐complexes. K values for complexes between eight phenethylamine enantiomers, namely ephedrine, pseudoephedrine, methylephedrine and norephedrine, and four different β‐cyclodextrin derivatives were determined by affinity capillary electrophoresis. The binding constants were calculated from the electrophoretic mobility values of the phenethylamine enantiomers at increasing concentrations of cyclodextrins in running buffer. Three different linear plotting methods (x ‐reciprocal, y ‐reciprocal, double reciprocal) and nonlinear regression were used for the determination of binding constants with β‐cyclodextrin, (2‐hydroxypropyl)‐β‐cyclodextrin, methyl‐β‐cyclodextrin and 6‐O‐α‐maltosyl‐β‐cyclodextrin. The cyclodextrin concentration in a 50 mM phosphate buffer pH 3.0 was varied from 0 to 12 mM. To investigate the influence of the binding constant values on the enantioseparation the observed electrophoretic selectivities were compared with the obtained K values and the calculated enantiomer‐cyclodextrin‐complex mobilities. The different electrophoretic mobilities of the temporarily formed complexes were crucial factors for the migration order and enantioseparation of ephedrine derivatives. To verify the apparent binding constants determined by capillary electrophoresis, a titration process using ephedrine enantiomers and β‐cyclodextrin was carried out. Furthermore, the isothermal titration calorimetry measurements gave information about the thermal properties of the complexes.     

环糊精衍生物在金属催化有机合成中的应用

综述了环糊精(包括α-环糊精,β-环糊精和γ-环糊精)衍生物在金属催化有机合成中的应用,主要包括其作为金属离子配体、金属纳米粒子稳定剂和反相相转移催化剂在氧化、水解、还原、偶联等金属催化反应中的应用.其中环糊精衍生物作为金属离子配体应用最广,由于环糊精部分与底物形成包结络合物,拉近了底物和具有催化活性的金属离子的距离,并固定了底物的反应部位,往往可以显著提高催化反应的反应速率,增强反应的区域选择性和对映选择性.     

Novel stationary phases for high-performance liquid chromatography analysis of cyclodextrin derivatives

Novel stationary phases were prepared for separation of cyclodextrins and cyclodextrin derivatives by bonding substituted aromatic groups (phenyl and naphthyl) to the silica gel matrix. Both the electron-withdrawing (nitro) and the hydrogen-donor/acceptor (amide or carbamide) substituents of the phenyl group play essential role in the separation of cyclodextrins and cyclodextrin derivatives. On the basis of the comparison of experimental data obtained on different columns the N-(4-nitrophenyl)-carbamide group bonded silica gel stationary phase was selected as the most effective one for analysis of cyclodextrin derivatives. Improved separation potency was observed for hydroxypropylated, methylated and several other cyclodextrin derivatives compared with the previously and presently used stationary phases. Owing to the strong retention of cyclodextrins and its derivatives on the selected column, detection of their decomposition products was easily achieved. Determination of unsubstituted, natural cyclodextrin as an impurity in the cyclodextrin derivatives was implemented. Identification and characterization of cyclodextrin derivatives in industrial products could also be performed.     

基于环糊精模板法的有机合成

利用"模板"理念综述了基于环糊精模板法的有机合成反应,并将基于环糊精模板法的有机合成反应分为两大类.第一类是基于环糊精"静态模板法"的有机合成,主要是指以环糊精刚性结构主、次面和空腔为模板进行的有机反应.其中,基于环糊精主次面的有机反应主要是体现了模板效应对空间结构的限定.而基于环糊精空腔的有机反应,重点是介绍那些利用环糊精空腔的手性和空间限定性等特点进行化学选择、区域选择和立体选择的反应,这体现了模板效应中的"信息"传递性.第二类有机反应则是基于"动态模板法",该模板自身是可调控的.其中,既可以具有可变空间构象的桥连环糊精二聚体为模板,也可以环糊精衍生物以及环糊精主客体包合物的自组装体系为模板.     

Comparison of Aqueous and 1-Octanol Solubility as well as Liquid–Liquid Distribution of Acyclovir Derivatives and Their Complexes with Hydroxypropyl-β-Cyclodextrin

The aim of the presented work is the comparison of aqueous and 1-octanol solubilities of different acyclovir derivatives and their hydroxypropyl-β-cyclodextrin inclusion complexes. The solubility measurements were carried out at different temperatures over the range 25–45 °C using water, 1-octanol, water saturated with 1-octanol, 1-octanol saturated with water, buffered aqueous solutions (pH = 5.5 and 7.0) and buffered aqueous solutions containing cyclodextrin as solvents. The aqueous solubilities of the compounds are very low but may be enhanced by complexation with hydroxypropyl-β-cyclodextrin, especially if the acyclovir derivatives have aromatic groups which may be included in the cyclodextrin cavity. The values of 1-octanol–water partition coefficients of acyclovir derivatives, obtained using extraction experiments, showed a similar sequence as the solubility results in 1-octanol. Additionally, some molecular mechanics and molecular dynamic calculations were performed to determine optimized structures of acyclovir derivative complexes with β-cyclodextrin treated as a model.     

Synthesis and inclusion properties study of some mono 6-amino ??-cyclodextrin dimers bridged by N,N-succinyldiamide linkers

Methylated and partially methylated cyclodextrin homo- and heterodimers linked by diamidosuccinic bridges were synthesised and their inclusion properties were evaluated using NMR and isothermic microcalorimetric measurements ITC. The selective binding of ligands, such as bisadamantyl derivatives, to the cavities of unprotected cyclodextrin dimers showed the equimolar formation of bidendate inclusion complexes (2:2, two ligand guest to two cavities host).     

Syntheses and characterisation of novel cyclodextrin vinyl derivatives from cyclodextrin-nitrophenol-derivatives

In this study novel reactive α-, β- and γ-cyclodextrin-esters (acrylate, pent-4-enoate and undec-10-enoate) have been synthesised and characterised. The syntheses were carried out by using nitrophenol-esters with the ability to form inclusion complexes with cyclodextrins, thereby aiming at a better control of the substitution degree and number of positional isomers of the cyclodextrin derivatives. Derivatives of α-, β- and γ-cyclodextrins modified with three different lengths of carbon-chains were successfully synthesised and characterised by MALDI-TOF MS, HPLC and LC-MS/MS, revealing some differences in LC elution patterns, substitution degrees and number of produced positional isomers. Differences were seen as an effect of changing the size of the cyclodextrin as well as the size of the side-chain being attached. The inclusion complexes between the nitrophenol esters and the different cyclodextrins were studied by ITC and selected ones by 2D ROESY NMR, showing some interesting differences in strength and structure of the complexes. These differences are speculated to be the origin of the different substitution patterns of the derivatives as observed by LC-MS/MS.     

Use of Chemically Bonded β‐Cyclodextrin Silica Stationary Phase for Liquid Chromatographic Separation of Structural Isomers

The retention behavior of five disubstituted benzene derivatives and two naphthalene derivatives is examined by using a chemically bonded β‐cyclodextrin silica stationary phase with the moiety containing the s‐triazine. The chromatographic results of five disubstituted benzene derivatives and two naphthalene derivatives show that effective separation is achieved on this stationary phase by high‐performance liquid chromatography. The results of the present investigation indicate that the formation of inclusion complexes plays a dominant role in the separation mechanism. However, the selectivity can be significantly enhanced by the n‐n interactions between the s‐triazine ring of the chemically bonded β‐cyclodextrin silica stationary phase and the aromatic ring of solutes. For example, the effective separation of the o‐, m‐, and p‐toluidine isomers on this stationary phase with the moiety containing the s‐triazine ring was better than on that of some β‐cyclodextrin bonded stationary phases without the moiety containing s‐triazine ring.     

β-cyclodextrin and its silyl derivative inclusion complexes and conjugates with medicine preparation “Ibuprofen” and its synthetic precursors

A possibility of formation of various inclusion complexes and conjugates of β-cyclodextrin and its silyl derivatives with the medicine preparation “Ibuprofen” and its synthetic precursors in dependence of nature of solvent and size of cyclodextrin cavity is demonstrated.     

Sulphamethizole-Cyclodextrin-Hydroxy Propylmethyl Cellulose Multicomponent Complexes

The effect of cyclodextrin complexation of sulphamethizole (SM) was studied. Two systems were prepared with two cyclodextrin derivatives, β-cyclodextrin (BCD) and hydroxypropyl-β-cyclodextrin (HPBCD): binary complexes and multicomponent systems (cyclodextrins and a hydroxylpropylmethyl cellulose K4M). Inclusion complexes were prepared by freeze-drying and characterized by thermal analysis (DSC) and X-ray diffractometry. The presence of the polymer in the solution increases the effect of cyclodextrins – specially BCD – on the solubility of SM. In solid state, binary inclusion complexes enhance the dissolution behaviour of SM but, from the multi-component complexes, the polymer controls the release of the drug. This revised version was published online in August 2006 with corrections to the Cover Date.     

Derivatized cyclodextrins for the separation of enantiomers in capillary electrophoresis

The use of cyclodextrin derivatives for the efficient separation of enantiomeric drugs is described. Hydroxypropylation, methylation or carboxymethylation of the cyclodextrin not only result in a better solubility of the cyclodextrin in aqueous solutions, but also favor, via additional hydrogen bonding, the stabilization of one of the cyclodextrin-analyte complexes. The influence of the background electrolyte on peak shape is also described here. Carboxymethylated cyclodextrin can be used in similar manner to uncharged cyclodextrins at low pH values (below 4). At pH values above 5, however, its charge also allows the separation of uncharged enantiomers as in a micellar-like system.     

Comparison of Different Di‐tert‐butyldimethyl‐Silylated Cyclodextrins as Chiral Stationary Phases in Capillary Gas Chromatography

Separation factors and thermodynamic data for the separation of various chiral analytes on different di‐O‐tert‐butyldimethyl‐silylated cyclodextrin derivatives are collected and described. Modifying the substitution pattern of the tert‐butyldimethylsilyl group in position 2 and 3 or changing from β‐ to γ‐cyclodextrin significantly affects the separation properties of the cyclodextrin derivatives.     

False positives and the detection of cyclodextrin inclusion complexes by electrospray mass spectrometry

The results of previous works that have claimed to detect cyclodextrin inclusion complexes via the “soft” ionization technique of electrospray ionization mass spectrometry are revisited. A more extensive study of cyclodextrin mixtures with amino acids and small peptides demonstrates that amino acid and peptide “complexes” are detected by electrospray mass spectrometry regardless of the presence (or not) of an aromatic moiety on the side chain. Amino acids that may be least likely to form hydrophobic inclusion complexes with cyclodextrin in solution generally show the most intense complex ions. The data suggest that these “complexes” are, in all likelihood, electrostatic adducts formed during the electrospray process. Systematic controls are suggested to ensure that “false positives” do not negate many of the claims concerning the detection of solution-derived noncovalent compounds.