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PubMed1992

13C-CP/MAS NMR studies of the cyclomalto-oligosaccharide (cyclodextrin) hydrates.

The 13C-CP/MAS NMR spectra of cyclomaltohexaose (alpha-cyclodextrin) hexahydrate, cyclomaltoheptaose (beta-cyclodextrin) "undecahydrate", cyclomalto-octaose (gamma-cyclodextrin) "octadecahydrate", and of the same materials at lower levels of hydration are compared with solution NMR data, structures obtained from single crystal diffraction studies, and with previous reports of the 13C-CP/MAS NMR spectra. The chemical shifts of the C-1 and C-4 resonances can be correlated with the conformation about the (1----4) linkage. The chemical shifts of the C-6 resonances are also sensitive to hydrogen-bonding interactions, as shown by the spectral changes on loss of water from the structures. The results suggest that, for resonances of carbon atoms close to a centre of significant conformational change, chemical shifts may be predicted on the basis of conformation alone, but for the resonances of more distant atoms, changes in chemical shift due to conformational change may be masked by the effects of alterations in the local environment.

Carbohydrate Sequence↗

PubMed1991

Chiral high-performance liquid chromatography of aromatic cyclic dipeptides using cyclodextrin stationary phases.

A series of enantiomers of cyclic and linear dipeptides containing aromatic amino acids was prepared and chromatographed on beta- and gamma-cyclodextrin (CD) columns. The retention times, separation factor alpha and resolution values were calculated. The relevance of the distance of the chiral center from the phenyl ring for chiral resolution was studied. A model was developed using X-ray crystallographic data for an inclusion complex of beta-CD and the enantiomers of cyclic (Phe-Gly).

Chromatography, High Pressure Liquid↗

PubMed1990

Polar-liquid, derivatized cyclodextrin stationary phases for the capillary gas chromatography separation of enantiomers.

A new class of hydrophilic, relatively polar liquid, cyclodextrin (CD) derivatives have been used as highly selective chiral stationary phases (CSPs) for capillary gas chromatography (GC). Several possible requirements for liquidity in CD derivatives are discussed. O-(S)-2-Hydroxypropyl derivatives of alpha-, beta-, and gamma-cyclodextrins were synthesized, exclusively characterized, permethylated, and evaluated for enantioselectivity. Seventy pairs of enantiomers were resolved. They represent a wide variety of structural types and classes of compounds including chiral alkyl amines, amino alcohols, epoxides, pyrans, furans, sugars, diols, esters, ketones, bicyclic compounds, alcohols, and so on. Many of these compounds were not aromatic and cannot be resolved on any known liquid chromatographic CSP. Often, these enantiomers had far less functionality than required for LC separation. General properties of these CSPs as well as possible insights into the separation mechanism are discussed.

Chromatography, Gas↗

PubMed1990

Substrate-dependent shift of optimum pH in porcine pancreatic alpha-amylase-catalyzed reactions.

Porcine pancreatic alpha-amylase (EC 3.2.1.1, abbreviated as PPA) hydrolyzes alpha-D-(1,4) glucosidic bonds in starch and amylose at random, and the optimum pH for the substrates is 6.9. The optimum pH, however, shifted to 5.2 for the hydrolytic reaction of low molecular weight oligosaccharide substrates such as p-nitrophenyl alpha-D-maltoside, gamma-cyclodextrin, maltotetaitol, and maltopentaitol. The optimum pH for the oligosaccharides consisting of more than five glucose residues, such as maltopentaose and maltohexaitol, was 6.9. From the analysis of the hydrolysates, it was clear that the shift of the optimum pH occurred only when the fifth subsite of PPA in the productive binding modes was occupied by a glucosyl residue of the substrates. The value of Km was independent of pH between 4 and 10 but that of kcat was dependent on pH. The pH profiles of kcat for the above substrates did not fit a simple bell-shaped curve predicted by a two-catalytic-group mechanism. Instead, they were well analyzed theoretically by three pK values and two intrinsic kcat values. Enthalpy changes for the three pK's (4.90, 5.35, and 8.55 at 30 degrees C) were determined from the temperature dependence of pH profiles for maltopentaitol and maltohexaitol to be 0.0, 2.87, and 7.33 kcal/mol, respectively. These results indicate that productive binding modes of the substrates directly affect the catalytic function of the enzyme. From the present thermodynamic analysis and reported three dimensional structure at the active site of PPA [Buisson, G. (1987) EMBO J. 6, 3909-3916], one can assume that a histidyl residue (101, 201, or 299) acts as a proton donor and two carboxyl groups (Asp 197, Glu 233, or Asp 300) act as proton donors or acceptors, and the productive binding mode covering the fifth subsite changes configurations between the catalytic residues and the glucosidic bond hydrolyzed and modulates kinetic parameters depending on pH.

Amylose↗

PubMed1992

Cyclodextrins as nasal absorption promoters of insulin: mechanistic evaluations.

The safety and effectiveness of cyclodextrins (CD) as nasal absorption promoters of peptide-like macromolecules have been investigated. The relative effectiveness of the cyclodextrins in enhancing insulin nasal absorption was found to be in the descending order of dimethyl-beta-cyclodextrin (DM beta CD) greater than alpha-cyclodextrin (alpha-CD) greater than beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) greater than gamma-cyclodextrin (gamma-CD). A direct relationship linking absorption promotion to nasal membrane protein release is evident, which in turn correlates well with nasal membrane phospholipid release. The magnitude of the membrane damaging effects determined by the membrane protein or phospholipid release may provide an accurate, simple, and useful marker for predicting safety of the absorption enhancers. In order to estimate further the magnitude of damage and specificity of cyclodextrin derivatives in solubilizing nasal membrane components, the enzymatic activities of membrane-bound 5'-nucleotidase (5'-ND) and intracellular lactate dehydrogenase (LDH) in the perfusates were also measured. HP beta CD at a 5% concentration was found to result in only minimal removal of epithelial membrane proteins as evidenced by a slight increase in 5'-ND and total absence of LDH activity. On the other hand, 5% DM beta CD caused extensive removal of the membrane-bound 5'-ND. Moreover, intracellular LDH activity in the perfusate increased almost linearly with time. The cyclodextrins are also capable of dissociating insulin hexamers into smaller aggregates, and this dissociation depends on cyclodextrin structure and concentration. Enhancement of insulin diffusivity across nasal membrane through dissociation may provide an additional mechanism for cyclodextrin promotion of nasal insulin absorption.

5'-Nucleotidase↗

PubMed1991

Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. I. A microcalorimetric study.

Solution calorimetry has been employed to evaluate the stability constants and enthalpy changes associated with complex formation between alpha-, beta, or gamma-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. Data from thermal titrations of the compounds were analyzed using nonlinear least squares. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative standard enthalpy change (delta H degrees). The standard entropy change (delta S degrees) was negative, except in the case of complexes formed with gamma-CD. Of the 13 compounds studied, only 2 formed complexes with 1:2 (compound:beta-CD) stoichiometry, terfenadine . HCl and cinnarizine . 2HCl. All the others formed 1:1 complexes. The structural effect on the stability constants, thermodynamics, and inclusion geometry was explored by relating the calorimetric results to the chemical structures of the guest molecules and the cavity sizes of the CD molecules. The results suggest that one of the phenyl groups of the diphenylmethyl functionality resides in the CD cavity and is in van der Waals contact with the inside wall of the CD cavity. In the case of alpha- and beta-CDs, van der Waals interaction dominates in the stabilization. On the other hand, the interaction between these compounds and gamma-CD is largely entropically driven. Adiphenine . HCl forms a more stable complex with beta-CD than proadifen . HCl, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl group on the rim of the CD ring can influence the strength of the binding interaction.

Calorimetry↗

PubMed1991

Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats.

The absorption enhancing effect of alpha-, beta-, and gamma-cyclodextrin (CD), dimethyl-beta-cyclodextrin (DM beta CD), and hydroxypropyl-beta-cyclodextrin (HP beta CD) on intranasally administered insulin was investigated in rats. Coadministration of 5% (w/v) DM beta CD to the insulin solution resulted in a high bioavailability, 108.9 +/- 36.4% (mean +/- SD, n = 6), compared to i.v. administration, and a strong decrease in blood glucose levels, to 25% of their initial values. Coadministration of 5% alpha-CD gave rise to an insulin bioavailability of 27.7 +/- 11.5% (mean +/- SD, n = 6) and a decrease in blood glucose to 50% of its initial value. The rate of insulin absorption and the concomitant hypoglycemic response were delayed for the alpha-CD-containing solution as compared to the DM beta CD preparation. The other CDs, HP beta CD (5%), beta-CD (1.8%), and gamma-CD (5%), did not have significant effects on nasal insulin absorption. DM beta CD at a concentration of 5% (w/v) induces ciliostasis as measured on chicken embryo tracheal tissue in vitro, but this effect is reversible. In conclusion, DM beta CD is a potent enhancer of nasal insulin absorption in rats.

Absorption↗

PubMed1992

Cyclomaltodextrin glucanotransferase from Bacillus circulans E 192. I. Purification and characterization of the enzyme.

The cyclomaltrodextrin glucanotransferase (CGTase) [1,4-alpha-D-glucan:4-alpha-D-(1,4-alpha-D-glucano)-transferase (cyclizing), EC 2.4.1.19] from Bacillus circulans E 192 has been purified to homogeneity by Cetavlon treatment, ammonium sulfate precipitation, DEAE Trisacryl M chromatography, Q Fast Flow chromatography, and affinity on beta-cyclodextrin-Sepharose 4B. Two isoenzymes were separated by FPLC on a Mono Q column. Their isoelectric points were estimated as 6.7 and 6.9 and they represented 13 and 87%, respectively, of the initial activity. Their molecular weight, pH, and temperature optima were estimated as 78,000, 5.5, and 60 degrees C, respectively. Kinetic parameters indicated that both enzymes had the same properties; they preferentially modified high-molecular-weight substrates to produce cyclodextrins. The apparent Vmax and Km values for soluble starch were 43 mumol of beta-cyclodextrin/min/mg of protein and 0.57% (w/v), respectively. Although this CGTase is not markedly thermostable, it is protected against heat denaturation by substrate, product, and/or calcium ions. The ratios of alpha-, beta-, and gamma-cyclodextrins produced have been determined as 1/7/2 in the initial phase of the reaction and 3/3/1 at equilibrium.

Amino Acid Sequence↗

PubMed1991

Sites and efficacy of photodamage by tin etiopurpurin in vitro using different delivery systems.

Photosensitization by tin etiopurpurin (SnET2) was determined in cell culture using sensitizer dissolved in ethanol or solubilized via three different delivery systems: Cremophor EL, gamma-cyclodextrin or Molecusol (a more water-soluble cyclodextrin derivative). Sensitizer uptake was substantially more efficient when the delivery systems were employed, in terms of intracellular level needed to lethally photosensitize cells. We observed photodamage at both membrane and mitochondrial loci, but the former was better correlated with loss of viability.

Animals↗

PubMed1991

Inhalational anesthetics stereochemistry: optical resolution of halothane, enflurane, and isoflurane.

Halothane (I), enflurane (II), and isoflurane (III), which are among the most important inhalation anesthetics, are currently administered as racemic mixtures. The pure enantiomers have not been described, and no analytical method for resolving the commercially available racemic mixtures has been reported. Complete optical resolution of (+/-)-I and (+/-)-III on per-n-pentylated alpha-cyclodextrin (Lipodex A) and of (+/-)-II and (+/-)-III on octakis(6-O-methyl-2,3-di-O-pentyl)-gamma-cyclodextrin capillary columns has been achieved, making rapid and convenient determination of enantiomeric ratios in samples of all three of these anesthetics possible.

Chromatography↗

PubMed1991

Cloning, nucleotide sequence, and enzymatic characterization of an alpha-amylase from the ruminal bacterium Butyrivibrio fibrisolvens H17c.

A Butyrivibrio fibrisolvens amylase gene was cloned and expressed by using its own promoter on the recombinant plasmid pBAMY100 in Escherichia coli. The amylase gene consisted of an open reading frame of 2,931 bp encoding a protein of 976 amino acids with a calculated Mr of 106,964. In E. coli(pBAMY100), more than 86% of the active amylase was located in the periplasm, and TnphoA fusion experiments showed that the enzyme had a functional signal peptide. The B. fibrisolvens amylase is a calcium metalloenzyme, and three conserved putative calcium-binding residues were identified. The amylase showed high sequence homology with other alpha-amylases in the three highly conserved regions which constitute the active centers. These and other conserved regions were located in the N-terminal half, and no similarity with any other amylase was detected in the remainder of the protein. Deletion of approximately 40% of the C-terminal portion of the amylase did not result in loss of amylolytic activity. The B. fibrisolvens amylase was identified as an endo-alpha-amylase by hydrolysis of the Phadebas amylase substrate, hydrolysis of gamma-cyclodextrin to maltotriose, maltose, and glucose and the characteristic shape of the blue value and reducing sugar curves. Maltotriose was the major initial hydrolysis product from starch, although extended incubation resulted in its hydrolysis to maltose and glucose.

Amino Acid Sequence↗

PubMed1992

Haloalkaliphilic maltotriose-forming alpha-amylase from the archaebacterium Natronococcus sp. strain Ah-36.

A haloalkaliphilic archaebacterium, Natronococcus sp. strain Ah-36, produced extracellularly a maltotriose-forming amylase. The amylase was purified to homogeneity by ethanol precipitation, hydroxylapatite chromatography, hydrophobic chromatography, and gel filtration. The molecular weight of the enzyme was estimated to be 74,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The amylase exhibited maximal activity at pH 8.7 and 55 degrees C in the presence of 2.5 M NaCl. The activity was irreversibly lost at low ionic strength. KCl, RbCl, and CsCl could partially substitute for NaCl at higher concentrations. The amylase was stable in the range of pH 6.0 to 8.6 and up to 50 degrees C in the presence of 2.5 M NaCl. Stabilization of the enzyme by soluble starch was observed in all cases. The enzyme activity was inhibited by the addition of 1 mM ZnCl2 or 1 mM N-bromosuccinimide. The amylase hydrolyzed soluble starch, amylose, amylopectin, and, more slowly, glycogen to produce maltotriose with small amounts of maltose and glucose of an alpha-configuration. Malto-oligosaccharides ranging from maltotetraose to maltoheptaose were also hydrolyzed; however, maltotriose and maltose were not hydrolyzed even with a prolonged reaction time. Transferase activity was detected by using maltotetraose or maltopentaose as a substrate. The amylase hydrolyzed gamma-cyclodextrin. alpha-Cyclodextrin and beta-cyclodextrin, however, were not hydrolyzed, although these compounds acted as competitive inhibitors to the amylase activity. Amino acid analysis showed that the amylase was characteristically enriched in glutamic acid or glutamine and in glycine.

Amino Acids↗

PubMed1990

Study of the interaction of clobazam with cyclodextrins in solution and in the solid state.

Inclusion complexes of clobazam with alpha-, beta-, gamma-cyclodextrins (CyDs) and heptakis(2.6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in aqueous solution and in the solid phase were studied by the solubility method, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry. In addition, inclusion complex of clobazam with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and the solid dispersion of clobazam with methyl cellulose (MC) in a ground mixture were investigated by IR, DSC and X-ray diffractometry. It was observed that DM-beta-CyD had the highest stability constant among the four CyDs in solution. Thermal and X-ray diffraction analyses showed that clobazam molecules existed in a molecularly dispersed state in the ground mixture of CyDs. Infrared spectra showed lower frequency shifts in the case of the ground mixtures of clobazam with natural CyDs, which can be attributed to the formation of hydrogen bonds between the two carbonyl groups of clobazam and hydroxyl groups of natural CyDs. In contrast, higher frequency shifts were observed in the case of the ground mixtures of clobazam with methylated CyDs and MC and these were considered to be due to the monomolecular dispersion of clobazam in a hydrophobic environment. The mode of interaction of clobazam with DM-beta-CyD was different from that with natural CyDs in the ground mixtures. Furthermore, the crystalline inclusion complex of clobazam with DM-beta-CyD was obtained by heating of the coprecipitate in vacuo at 120 degrees C for 1 h.

Anti-Anxiety Agents↗

PubMed1992

Specific inhibition by cyclodextrins of raw starch digestion by fungal glucoamylase.

alpha-, beta-, and gamma-cyclodextrins (CDs) completely inhibited raw starch digestion by glucoamylase I (GA I, MW 90,000) from Aspergillus awamori var. kawachi, and inhibited by 85% the raw starch adsorption of GA I at the CD concentrations of 1-5 mM. CDs at 1-5 mM did not inhibit gelatinized starch hydrolysis by GA I, but at the concentration of 50 mM, they inhibited such hydrolysis slightly. GA I was specifically adsorbed onto CD-Sepharose 6B, but glucoamylase I' (GA I', MW 73,000), which does not adsorb onto or digest raw starch, from the same strain was not adsorbed onto that gel. The adsorption of the glucoamylases onto raw starch and CD-Sepharose 6B was correlated to their digestion of raw starch. The hydrophobic adsorption of GA I onto CDs and raw starch occurred competitively at the Cp region, which is on the C-terminal side of Gp-I in the site for raw starch affinity of GA I, and inclusion complexes were formed.

Adsorption↗

PubMed1992

[Comparative characteristics of cyclodextrin glycosyltransferases from various groups of microorganisms].

Cyclodextrin glycosyltransferases (CGT-ase, 1.4-alpha-glucanotransferase, cyclizing, EC 2.4.1.19) produced by some thermophilic, alkalophilic and mesophilic bacterial strains, were isolated and characterized. It was shown that thermophilic and mesophilic CGT-ases represent a mixture of alpha-, beta- and gamma-cyclodextrins (CD), alpha-cyclodextrin being the predominant component. Alkalophilic enzymes produce only beta-CD and are able to produce CD not only from starch but also from maltose, melibiose, maltotriose, amylose and amylopectin. The optimal conditions for the catalytic activity of the enzymes were determined. It was found that calcium, magnesium and zinc ions have a beneficial effect on the specific activity of these enzymes. The amino acid composition of the enzymes was studied.

Amino Acids↗

PubMed1992

Improvement of oral bioavailability of fenbufen by cyclodextrin complexations.

The interactions of fenbufen (FB) with alpha-, beta-, gamma-cyclodextrins (CyDs) were studied in aqueous solution and in solid state. beta-CyD formed water soluble complex with FB in the molar ratio of 1:2 (guest:host). The solid complex of FB with alpha-CyD was obtained in the molar ratio of 1:2 (guest:host), while the same with gamma-CyD was obtained as 1:1 ratio. The dissolution rate and bioavailability of FB were significantly increased by the formation of inclusion complexes (alpha greater than gamma-CyD complex). CyDs had no effect on the metabolic time of FB forming two active metabolites, and the bioavailability of metabolites was also increased by complexation of FB with CyDs. The bitter taste of FB powder was reduced by alpha-CyD complexation. The enhanced bioavailability and reduced bitterness of FB by CyD complexations suggested the possibility of applying FB in smaller doses with fewer side-effects.

Animals↗

PubMed1992

Hydroxypropylcyclodextrins in parenteral use. I: Lipid dissolution and effects on lipid transfers in vitro.

Hydroxypropyl ethers of cyclodextrins form water-soluble inclusion complexes with lipids. Of the three hydroxypropylcyclodextrins examined, hydroxypropyl-alpha-cyclodextrin had limited specificity for phospholipids, and hydroxypropyl-beta-cyclodextrin had limited specificity for cholesterol, and hydroxypropyl-gamma-cyclodextrin was nonspecific. The formation of inclusion complexes was found to be a fast and reversible process in which complexation of cholesterol did not inhibit its oxidation by cholesterol oxidase, and cholesterol of the erythrocyte membrane could be exchanged within a minute for cholesteryl methyl ether which was in the inclusion complex. Thus, hydroxypropylcyclodextrin in the circulation may catalyze the transport of lipids in the direction of equilibrium distribution.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1992

Hydroxypropylcyclodextrins in parenteral use. II: Effects on transport and disposition of lipids in rabbit and humans.

Hydroxypropyl ethers of cyclodextrins, after parenteral administration, come into contact with lipids in tissues and in circulation and form water-soluble inclusion complexes with these lipids. A single intravenous administration of hydroxypropyl-beta-cyclodextrin to a hereditary hyperlipidemic Watanabe rabbit slightly and temporarily decreased the level of total cholesterol in serum. Single injections of hydroxypropyl-alpha-cyclodextrin and of the corresponding gamma-homologue, both of which are less potent solubilizers of cholesterol, had lesser effects. Repeated administration of hydroxypropyl-beta-cyclodextrin to rabbits led to a gradual increase in total cholesterol in circulation and eventually to a slight relief of atherosclerotic lesions in the thoracic aorta. The only untoward effects of repeated treatments (total doses of up to 40 g/kg) were vacuoles in cells of proximal convoluted tubules in the kidneys. Repeated administration also strongly increased cholesterol in urine, probably because of excretion of the soluble cholesterol-hydroxypropyl-beta-cyclodextrin complex. Proteins in urine increased significantly, whereas triglycerides increased only moderately after repeated administrations. Intravenous infusion of hydroxypropyl-beta-cyclodextrin into a patient with hypervitaminosis A led to a release of liver-stored retinoids into serum in quantities much higher than those that could be directly solubilized by hydroxypropyl-beta-cyclodextrin. Levels of total cholesterol in the circulation of this patient decreased during the infusion. Thus, hydroxypropylcyclodextrins may serve as artificial lipid carriers in the circulation, and because the exchanges that involve inclusion complexation occur very quickly, the presence of hydroxypropylcyclodextrins in organisms may catalytically augment the establishment of equilibria in lipid distribution.

2-Hydroxypropyl-beta-cyclodextrin↗