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PubMed2000

Crystal structure of alkalophilic asparagine 233-replaced cyclodextrin glucanotransferase complexed with an inhibitor, acarbose, at 2.0 A resolution.

The product specificity of cyclodextrin glucanotransferase (CGTase) from alkalophilic Bacillus sp. #1011 is improved to near-uniformity by mutation of histidine-233 to asparagine. Asparagine 233-replaced CGTase (H233N-CGTase) no longer produces alpha-cyclodextrin, while the wild-type CGTase from the same bacterium produces a mixture of predominantly alpha-, beta-, and gamma-cyclodextrins, catalyzing the conversion of starch into cyclic or linear alpha-1,4-linked glucopyranosyl chains. In order to better understand the protein engineering of H233N-CGTase, the crystal structure of the mutant enzyme complexed with a maltotetraose analog, acarbose, was determined at 2.0 A resolution with a final crystallographic R value of 0.163 for all data. Taking a close look at the active site cleft in which the acarbose molecule is bound, the most probable reason for the improved specificity of H233N-CGTase is the removal of interactions needed to form a compact ring like a-cyclodextrin.

Acarbose↗
PubMed1992

Cyclization characteristics of cyclodextrin glucanotransferase are conferred by the NH2-terminal region of the enzyme.

Cyclodextrin glucanotransferase (CGTase; EC 2.4.1.19) is produced mainly by Bacillus strains. CGTase from Bacillus macerans IFO3490 produces alpha-cyclodextrin as the major hydrolysis product from starch, whereas thermostable CGTase from Bacillus stearothermophilus NO2 produces alpha- and beta-cyclodextrins. To analyze the cyclization characteristics of CGTase, we cloned different types of CGTase genes and constructed chimeric genes. CGTase genes from these two strains were cloned in Bacillus subtilis NA-1 by using pTB523 as a vector plasmid, and their nucleotide sequences were determined. Three CGTase genes (cgt-1, cgt-5, and cgt-232) were isolated from B. stearothermophilus NO2. Nucleotide sequence analysis revealed that the three CGTase genes have different nucleotide sequences encoding the same amino acid sequence. Base substitutions were found at the third letter of five codons among the three genes. Each open reading frame was composed of 2,133 bases, encoding 711 amino acids containing 31 amino acids as a signal sequence. The molecular weight of the mature enzyme was estimated to be 75,374. The CGTase gene (cgtM) of B. macerans IFO3490 was composed of 2,142 bases, encoding 714 amino acids containing 27 residues as a signal sequence. The molecular weight of the mature enzyme was estimated to be 74,008. The sequence determined in this work was quite different from that reported previously by other workers. From data on the three-dimensional structure of a CGTase, seven kinds of chimeric CGTase genes were constructed by using cgt-1 from B. stearothermophilus NO2 and cgtM from B. macerans IFO3490. We examined the characteristics of these chimeric enzymes on cyclodextrin production and thermostability. It was found that the cyclization reaction was conferred by the NH2-terminal region of CGTase and that the thermostability of some chimeric enzymes was lower than that of the parental CGTases.

Amino Acid Sequence↗
PubMed1996

Method development in liquid chromatography with a charged cyclodextrin additive for chiral resolution of rac-amlodipine utilising a central composite design.

A negatively charged derivative of beta-cyclodextrin, sulphobutyl ether-beta-cyclodextrin (SBE-beta-CD), was examined as a chiral mobile phase additive in reversed-phase high-performance liquid chromatography for the enantiomeric resolution of the calcium channel blocker rac-amlodipine. Theoretical and practical aspects are discussed for setting up a central composite design applicable to any analytical method. These include the correct location of factor points for maintaining orthogonality within the design and the augmentation of centrepoint experiments to allow a larger factor space by increasing the distance of axial star points. Optimised separation was achieved using a reverse-phase column with eluent comprising: acetonitrile (ACN)-potassium dihydrogen phosphate (pH 3.93) containing 2.66 mM SBE-beta-CD (26.5:73.5% v/v) at a flow rate of 1.0 ml/min. This yielded a Kaiser peak separation index, Pi = 0.96, at tR2 = 52 min with satisfactory reproducibility, relative standard deviation values: tR1, 0.39%; tR2, 0.47% (n = 5). These experimental results were in excellent agreement with those predicted by the SAS software package for a chromatographic response function model. Multiple regression analysis in four dimensions, with three response models based on Rs, Pi, and a function of Pi, produced response surfaces which revealed zones of optimum robustness and illustrated the interactions involved between the key chromatographic factors. Putative proposals for a mechanism involving the interaction of each of the positively charged enantiomers with the negatively charged cyclodextrin are also discussed. These examine the possibility of ion-pairing and inclusion phenomena to account for the excellent resolution observed.

Amlodipine↗
PubMed1999

Estimation of the pH-independent binding constants of alanylphenylalanine and leucylphenylalanine stereoisomers with beta-cyclodextrin in the presence of urea.

The separation of stereoisomers, particularly enantiomers, is important when their physiological activity differs. We have resolved the four stereoisomers each of alanylphenylalanine (Ala-Phe) and of leucylphenylalanine (Leu-Phe) by capillary electrophoresis using beta-cyclodextrin as a buffer additive and urea to enhance its solubility. A study of the influence of pH and beta-cyclodextrin concentration on the separations showed that weak inclusion complexes were formed between the dipeptides and chiral selector. It was found that pH could alter the migration order of enantiomers L-Ala-L-Phe and D-Ala-D-Phe, as well as L-Leu-L-Phe and D-Leu-D-Phe; however, there was no change in order for the other pairs of optical isomers. Electrophoretic mobility data were used to estimate the acid dissociation constants of the dipeptide isomers at pH < 7 with no chiral selector present. By varying the concentration of beta-cyclodextrin, the chiral selector, the binding constants of Ala-Phe and Leu-Phe optical isomers in their fully protonated and zwitterionic forms were estimated. For the four Ala-Phe stereoisomers, K = 42-66 M(-1) and 4-41 M(-1) for the cationic and zwitterionic forms, respectively. For the four Leu-Phe stereoisomers, K = 43-94 M(-1) and 1-28 M(-1) for the cationic and zwitterionic forms, respectively.

Buffers↗
PubMed1999

Separation of resin acids using cyclodextrin-modified capillary electrophoresis.

A cyclodextrin-modified capillary electrophoretic method has been developed for the analysis of eleven common resin acids using a pH 4.5, 20 mM sodium acetate buffer containing 10% acetonitrile, 20 mM methyl-beta-cyclodextrin (MECD) and 30 mM sulfobutylether-beta-cyclodextrin (SBCD) as buffer modifiers. At pH below their pKa (< 5.7-6.4) the resin acids were virtually unionized and insoluble; however, they formed water-soluble inclusion complexes with MECD (20 mM) or SBCD (30 mM) even at pH 4.5. The analytes were separated in 25 min and, with the exception of two pairs, 12- or 14-chlorodehydroabietic/12,14-dichlorodehydroabietic acid and dehydroabietic/palustric acid, the remaining resin acids were baseline-separated. Analysis time was significantly shortened (< 12 min) at pH 9.25 using 30 mM SBCD and 20 mM MECD in 20 mM sodium borate. Resin acids were baseline-separated with the exception of two pairs, pimaric/sandaracopimaric acid and 12- or 14-chlorodehydroabietic/abietic acid. The addition of 7.5% methanol to the running buffer resolved the abietic acid peak. Both HPLC and micellar capillary electrokinetic chromatography using 20 mM deoxycholic acid, 10% acetonitrile in 20 mM sodium borate, pH 9.25, failed to resolve the resin acids. The simple capillary electrophoretic method developed would be useful for the rapid separation and characterization of several important resin acids in pulp mill effluents and other contaminated samples.

Acetonitriles↗
PubMed2002

Capillary electrophoretic study of interactions of metal ions with crown ethers, a sulfated beta-cyclodextrin, and zwitterionic buffers present as additives in the background electrolyte.

Stability constants of K, Na, Ca, and Ba with 18-crown-6, K, Na, Li with sulfated beta-cyclodextrin and K, Li, Ca, Mg, Sr, and Ba ions with ([2-hydroxy-1,1-bis(hydroxymethyl) ethyl]-amino)-1-propanesulfonic acid (TAPS) were determined by capillary electrophoresis and computed using a general least squares minimizing program CELET. The results for 18-crown-6 agreed well with those evaluated by graphical methods or reported in the literature. Previously unknown stability constants of sulfated beta-cyclodextrins and TAPS determined for alkali and alkaline earth metals show that sulfated beta-cyclodextrin interacts with monovalent metals allowing to manipulate their effective mobility. It interacts stronger with divalent metal cations. TAPS, as zwitterionic buffer widely used in various analytical, biochemical and other applications, forms complexes with alkali and alkaline earth cations, and although the stability constants are rather low, the equilibria should be taken into account when TAPS is used and metal cations are present in solution at the same time.

Buffers↗
PubMedDate not supplied

Effect of column temperature and nitrogen flow rate on the separation of cis-permethrinic acid isomers on a (2,3,6-tri-O-methyl)-beta-cyclodextrin coated capillary column.

The separation efficiency of a capillary column coated with (2,3,6-tri-O-methyl)-beta-cyclodextrin was determined at the temperature and flow rate ranges of 80-120 degrees C and 0.3-1.5 mL/min respectively using (+) and (-) cis-permethrinic acid methylesters as test compounds. The dependence of the retention differences, sum of peak widths and separation factor on the temperature and flow rate was calculated with step regression analysis. The column exhibited acceptable isomer separation capacity at each temperature and flow rate proving the excellent separation power of the cyclodextrin coating. The differences between the retention times of isomers depended on the logarithm and on the reciprocal value of temperature, the effect of flow rate was negligible. The sum of their peak widths depended reciprocally on the temperature and logarithmically on the flow rate, the impact of temperature being higher than that of flow rate. The significant impact of the reciprocal value of temperature can be explained by the inclusion complex formation between cyclodextrin and cis-permethrinic acid methylester isomers. The resolution depended on the square of column temperature and flow rate, indicating local optimums at each temperature and flow rate.

Chromatography, Gas↗
PubMed1994

Molecular modelling of the inclusion complexes between beta-cyclodextrin and (R)/(S)-methylphenobarbitone and its application to HPLC.

Molecular modelling of beta-cyclodextrin and optimisation of its potential energy suggests that a favoured conformation is that distorted from a symmetrical torus. The inclusion of water molecules into the torus cavity simulates the increased stability in an aqueous solvent. Complexes of beta-cyclodextrin with (R)- and (S)-enantiomers of methylphenobarbitone have been modelled and energetically optimised by the application of molecular mechanics. The simulations suggests that the guest molecules adopt an orientation in which the phenyl ring is projected into the torus cavity, with in each case the plane of the ring parallel to a longer axis of the distorted torus and slightly displaced from the axis through the torus cavity. It is suggested that the asymmetry in the macrocyclic ring contributes to chiral recognition as a result of additional discriminatory binding to the barbiturate ring residue of each enantiomer, which occupy different 3D geometries. The enantiomers form complexes of different minimum potential energies. The resulting difference in complex stability can be related to the behaviour of beta-cyclodextrin, as a mobile phase additive in reverse-phase HPLC to effect chiral separation of rac-methylphenobarbitone during chromatography.

Chromatography, High Pressure Liquid↗
PubMed1994

Neutral and anionic cyclodextrins in capillary zone electrophoresis: enantiomeric separation of ephedrine and related compounds.

Two methods for the enantiomeric separation of chiral ephedrine alkaloids (ephedrine, methylephedrine, methylpseudoephedrine and norephedrine) by capillary zone electrophoresis in uncoated capillaries were developed. Both methods were optimized to more than 100,000 theoretical plate numbers. The first method used a neutral cyclodextrin (CD) derivative: heptakis (2,6-di-O-methyl)-beta-cyclodextrin at an acidic pH of 2.5 (20 mM phosphate buffer) at an 18 mM concentration. The second used a newly developed acidic CD derivative, the tetrakis[6-O-(4-sulfobutyl)]-beta-cyclodextrin sodium salt. The benefits of this new reagent for the chiral separation are a wide range of basic pH available for the enantiomeric resolution. It is also useful for other cases, e.g. preventing adsorption without additives.

Anions↗
PubMed1995

Further study on the use of uncharged beta-cyclodextrin polymer in capillary electrophoresis: enantiomeric separation of some alpha-hydroxy acids.

Uncharged beta-cyclodextrin polymer was used as chiral selector for the enantiomeric separation of some alpha-hydroxy acids by capillary electrophoresis. Complexation and enantiomeric resolution of mandelic acid, m-hydroxy and p-hydroxymandelic acid, 3,4-dihydroxymandelic acid, as well as 2- and 3-phenyllactic acid were studied, changing the concentration of the beta-cyclodextrin polymer added to the background electrolyte at different pH in the range of 4.5-7. Furthermore, the effects of the concentration of the background electrolyte, column temperature, and applied voltage on chiral resolution were also examined. The best enantiomeric separations were obtained using a background electrolyte at pH 6 containing 100 mg/mL of beta-cyclodextrin polymer.

Cyclodextrins↗
PubMed1997

Electrokinetic chromatography employing an anionic and a cationic beta-cyclodextrin derivative.

beta-Cyclodextrin, 1, can act as a chiral buffer additive in capillary zone electrophoresis (CZE) owing to its ability to form diastereomeric complexes with the enantiomers of ionic compounds. Reaction of 1 with 2,3-epoxy-propyltrimethylammonium chloride gave preponderantly 6-O-(2-hydroxy-3-trimethylammoniopropyl) derivatives (2) of varying degrees of substitution (d.s.). Analogous reaction of 1 with 1,3-propanesultone yielded 6-O-(sulfo-n-propyl) derivatives (SPE-beta-CD, 3) of varying d.s. The purity and the d.s. of 2 and 3 were determined by 1H NMR and electrospray ionization mass spectrometry (ESI-MS). These charged beta-cyclodextrin derivatives were used for the chromatographic enantiomer separation of a series of neutral barbiturates, of chlorthalidone, terbutaline, warfarin, salbutamol and brompheniramine by cyclodextrin electrokinetic chromatography (CD-EKC). During the separation of chlorthalidone with 3 as chiral additive, a reversible interconversion of the enantiomers (enantiomerization) was observed at temperatures below 20 degrees C.

Anions↗
PubMed1998

Isolation and characterization of beta-cyclodextrin sulfates by preparative gradient polyacrylamide gel electrophoresis, capillary electrophoresis and electrospray ionization - mass spectrometry.

A beta-cyclodextrin sulfate mixture has been fractionated using discontinuous gradient polyacrylamide gel electrophoresis. Semidry electrotransfer of the sample onto a positively charged nylon membrane and visualization of a portion of this membrane with Alcian blue stain showed multiple bands. The bands were cut from the remaining portion of the membrane and after washing with 8 M urea, the beta-cyclodextrin sulfate fractions were eluted with 2 M sodium chloride and dialyzed. Analysis of each fraction using high resolution analytical gradient polyacrylamide gel electrophoresis as well as capillary electrophoresis, using indirect detection, showed some of the fractions to be pure while others were mixtures. Each beta-cyclodextrin sulfate fraction was complexed with a basic synthetic peptide and analyzed by electrospray ionization mass spectrometry to define the mass of the components in each mixture and thereby to determine the purity of each sample.

Carbohydrate Sequence↗
PubMed2002

Protective effect of sulfobutyl ether beta-cyclodextrin on DY-9760e-induced hemolysis in vitro.

The hemolytic behavior of a novel cytoprotective agent, DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) was investigated using rabbit erythrocytes. Further, the effects of water-soluble cyclodextrin derivatives, such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and sulfobutyl ether of beta-cyclodextrin (SBE-beta-CyD), on the hemolytic activity of DY-9760e were studied. DY-9760e induced hemolysis at concentrations >0.2-0.3 mM in phosphate buffered saline (PBS) of pH 4.0 and 6.0, where DY-9760e is predominantly in dicationic and monocationic forms, respectively. The hemolytic activity of the monocationic DY-9760e was higher than that of the dicationic species, and the hemolysis at pH 4.0 involved the formation of methemoglobin. DY9760e induced the morphological change of erythrocytes towards membrane invagination at both pH 4.0 and 6.0. SBE7-beta-CyD significantly suppressed the DY-9760e-induced hemolysis and morphological change at both pH 4.0 and 6.0, as well as the formation of methemoglobin at pH 4.0. On the other hand, HP-beta-CyD suppressed only the hemolysis, but neither the morphological change nor the formation of methemoglobin. In addition, the inhibitory effect of SBE7-beta-CyD on the hemolysis was greater than that of HP-beta-CyD. The superior inhibitory effect of SBE7-beta-CyD on the DY-9760-induced hemolysis, the morphological change, and the formation of methemoglobin may be attributable to the formation of a stable inclusion complex with DY-9760e and to the weaker hemolytic activity of SBE7beta-CyD than HP-beta-CyD. These results suggest potential use of SBE7-beta-CyD as a parenteral carrier for DY-9760e.

Animals↗
PubMed2002

Preliminary pharmacokinetic study of different preparations of acyclovir with beta-cyclodextrin.

Acyclovir has absorption problems, because of its low solubility and/or its saturable absorption mechanism, that take place in the small intestine in a passive, variable, and incomplete manner. The oral bioavailability of acyclovir is thereby affected and reaches only 15-30%. The purpose of this study was to investigate the possibility of increasing the oral availability of acyclovir by forming inclusion complexes of acyclovir with beta-cyclodextrin. Acyclovir, its complex (1:1) with beta-cyclodextrin (acyclovir-beta-cyclodextrin complex), and a 50:50 mixture of acyclovir and the inclusion complex (acyclovir/complex mixture) as an aqueous suspension were administered intraintestinally to male Sprague-Dawley rats in doses equivalent to an acyclovir dose of 75 mg/kg. Sequential samples of plasma were taken by microdialysis. The samples were analyzed by high-performance liquid chromatography with ultraviolet detection. Plasma concentration versus time curves show that the complex and the mixture of acyclovir/complex have a higher bioavailability and a pharmacokinetic profile than that of the drug itself.

Acyclovir↗
PubMed2003

Inhibitory effect of sulfobutyl ether beta-cyclodextrin on DY-9760e-induced cellular damage: In vitro and in vivo studies.

The effects of water-soluble beta-cyclodextrin derivatives (beta-CyDs), such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and sulfobutyl ether beta-cyclodextrin (SBE7-beta-CyD) on cytotoxicity of DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) toward human umbilical vein endothelial cells (HUVECs) in vitro and vascular damage of the auricular vein of rabbits by DY-9760e in vivo were investigated. The spectroscopic study revealed that of the four beta-CyDs SBE7-beta-CyD forms the most stable inclusion complex in phosphate-buffered saline, probably because of a synergetic effect of hydrophobic and electrostatic interactions. beta-CyDs inhibited DY-9760e-induced cell death toward HUVECs in an order of G(2)-beta-CyD < beta-CyD < HP-beta-CyD < SBE7-beta-CyD, which was consistent with the order of the magnitude of stability constants. When the DY-9760e solution was infused into the auricular vein of rabbits for 24 h, SBE7-beta-CyD suppressed a DY-9760e-induced irritation such as thrombus, desquamation of the endothelium vasculitis, and perivasculitis. The present data indicated that SBE7-beta-CyD formed an inclusion complex with DY-9760e in a buffer solution and possessed the protective effect on DY-9760e-induced cytotoxicity toward HUVECs and vascular damage in rabbits. These results suggested potential use of SBE7-beta-CyD as a parenteral carrier for DY-9760e.

Animals↗
PubMed1988

Utilization of diethyl-beta-cyclodextrin as a sustained-release carrier for isosorbide dinitrate.

Heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (2) was prepared and its physicochemical properties, such as aqueous solubility and surface activity, were compared with those of beta-cyclodextrin (1) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (3). A possible utility of 2 as a sustained-release drug carrier was examined using a water-soluble drug, isosorbide dinitrate. The dissolution and release rates of isosorbide dinitrate from capsule and tablet forms were significantly retarded by the complexation with 2. The sustained-release pattern of isosorbide dinitrate was produced for a long period after the oral administration of a single dose of capsule or tablet containing the 2 complex to rats. The results indicated that 2 may serve as a hydrophobic drug carrier for sustained-release of isosorbide dinitrate.

Animals↗
PubMed1990

Design and in vitro evaluation of slow-release dosage form of piretanide: utility of beta-cyclodextrin:cellulose derivative combination as a modified-release drug carrier.

To modify the release rate of piretanide, a potent loop diuretic, a double-layer tablet was designed, and in vitro release was evaluated. For a rapidly releasing portion, hydrophilic beta-cyclodextrin derivatives were employed to form a water-soluble complex with piretanide. For a sustained-release portion, cellulose derivatives were used to provide appropriate hydrophobicity. The release rate of piretanide in the pH range 1.2-6.8 was automatically monitored by a pH-changeable dissolution testing apparatus. The low solubility of piretanide in acidic medium was significantly improved by complexations with dimethyl-beta-cyclodextrin (DM-beta-CyD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The pH-independent slow release was attained by use of hydroxypropylcellulose (HPC):ethylcellulose (EC) matrices. Then, an optimal formulation of a double-layer tablet was obtained by the combination of each fraction. For example, the tablet consisting of the [DM-beta-CyD/(HPC:EC)] system in the weight ratio [1/3(1:3)] provided a sufficiently slow release of the drug over a period of 8 h in a wide pH region following an initial rapid dissolution.

Cellulose↗
PubMed1992

Enhanced rectal absorption and reduced local irritation of the anti-inflammatory drug ethyl 4-biphenylylacetate in rats by complexation with water-soluble beta-cyclodextrin derivatives and formulation as oleaginous suppository.

To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated and compared with the use of the parent beta-cyclodextrin (beta-CyD). Among the three beta-CyDs, HP-beta-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of beta-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and beta-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of beta-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When beta-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-beta-CyD (approximately 26% of dose) and DM-beta-CyD (approximately 21% of dose), compared with beta-CyD (approximately 5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic beta-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗