Synthesis and analytical characterization of the sodium salt of heptakis(2-O-methyl-3,6-di-O-sulfo)cyclomaltoheptaose, a chiral resolving agent candidate for capillary electrophoresis

A pure, single isomer, strong electrolyte chiral resolving agent candidate for capillary electrophoresis, the sodium salt of heptakis(2-O-methyl-3,6-di-O-sulfo)cyclomaltoheptaose has been synthesized on the 100-g scale, in greater than 97% purity, through heptakis(2,6-di-O-tert-butyldimethylsilyl)cyclomaltoheptaose, heptakis(2-O-methyl-3,6-di-O-tert-butyldimethylsilyl)cyclomaltohep taose and heptakis(2-O-methyl)cyclomaltoheptaose intermediates. The structural identity of each intermediate and the final product was conclusively established by high-resolution MALDI-TOF mass spectrometry, variable-temperature 1H and 13C NMR spectroscopy and X-ray crystallography. The purity of each intermediate and the final product was determined by gradient high-performance liquid chromatography (HPLC) and indirect UV detection capillary electrophoresis.     

A structural and thermal investigation of the inclusion of parabens in heptakis(2,6-di-O-methyl)cyclomaltoheptaose

The structures of the inclusion complexes formed by heptakis(2,6-di-O-methyl)cyclomaltoheptaose and methyl-, ethyl-, propyl- and butyl parabens have been solved and analysed by X-ray diffraction. Each inclusion complex crystallises in the space group P2(1)2(1)2(1) with Z=4 and a host-to-guest ratio of 1:1. However the packing arrangements and modes of guest inclusion are not equivalent for the four structures. The analytical data indicated that two isostructural pairs, the methyl- and ethyl-paraben complexes, have similar cell parameters that differ from those of the propyl- and butyl paraben complexes. The results of thermogravimetric analysis and differential scanning calorimetry of the complexes are also reported.     

Nonaqueous synthesis of a selectively modified, highly anionic sulfopropyl ether derivative of cyclomaltoheptaose (beta-cyclodextrin) in the presence of 18-crown-6

A highly anionic cyclomaltooligosaccharide (cyclodextrin, CD) derivative containing sulfopropyl functional groups on the primary face of the CD was synthesized. Heptakis(2,3-di-O-methyl)cyclomaltoheptaose [heptakis(2,3-di-O-methyl)-beta-cyclodextrin] was reacted with 1,3-propane sultone and potassium hydride (KH) in anhydrous tetrahydrofuran in the presence of 18-crown-6 to yield highly substituted potassium heptakis(2,3-di-O-methyl-6-O-sulfopropyl)cyclomaltoheptaose [heptakis(KSPDM)-beta-CD] with an average degree of substitution (DSCE) of 6.9 as determined by inverse detection capillary electrophoresis (CE). The principal species in the product is the fully substituted heptakis(KSPDM)-beta-CD. Complete NMR assignments of the hydrogen and carbon atoms are made using a combination of gCOSY and gHSQC. In the absence of 18-crown-6, the reaction generates a mixture of multiply charged derivatives with average DSCE of 4.1. The possible roles of the crown ether in the reaction are discussed. The ROESY NMR spectrum of the inclusion complex that forms between heptakis(KSPDM)-beta-CD and 2-naphthoic acid in D2O reveals that 2-naphthoic acid inserts with the carboxyl group toward the derivatized primary rim of the cyclodextrin.     

A sensitive and specific enzyme immunoassay for the detection of methyl ether derivatives of cyclomaltoheptaose

We have raised antibodies against two methylated derivatives of beta-CD, heptakis(2,6-di-O-methyl)cyclomaltoheptaose (Dimeb) and heptakis(2,3,6-tri-O-methyl)cyclomaltoheptaose (Trimeb). These antibodies were used to develop two specific and sensitive enzyme immunoassays, presenting a detection limit close to 500 and 30 pg/mL for Trimeb and Dimeb, respectively. Cross reactivities of different linear and cyclic maltooligosaccharides were investigated, demonstrating a high specificity against the structural features of the secondary hydroxyls rim. Several commercial Dimeb samples, containing different mixtures of partially methylated beta-cyclodextrin derivatives including RAMEB, which contains only a few amount of pure Dimeb, could be easily evaluated by the Dimeb immunoassay. Both of these assays have been shown to allow accurate measurement in plasma and urine, thus appearing as useful tools for further applications in biological material.     

Water soluble heptakis(6-deoxy-6-thio)cyclomaltoheptaose capped gold nanoparticles via metal vapour synthesis: NMR structural characterization and complexation properties

The complexation of heptakis(6-deoxy-6-thio)cyclomaltoheptaose to gold nanoparticles prepared by using the Metal Vapour Synthesis (MVS) led to water soluble gold nanoaggregates, thermally stable at 25 °C. The role of gold concentration in the MVS-derived starting solution as well as of the cyclodextrin to gold molar ratio on the size of cyclodextrin-capped gold nanoparticles were investigated. The ability of cyclodextrin bonded to gold nanoparticles to include deoxycytidine was also probed in comparison with that of 1-thio-β-d-glucose sodium salt.     

New cyclomaltoheptaose (beta-cyclodextrin) derivative 2-O-(2-hydroxybutyl)cyclomaltoheptaose: preparation and its application for the separation of enantiomers of drugs by capillary electrophoresis

A new soluble cyclomaltoheptaose (cyclodextrin) derivative, 2-O-(2-hydroxybutyl)cyclomaltoheptaose [2-O-(2-hydroxybutyl)-beta-cyclodextrin, 2-HB-beta-CD], was prepared and studied as an efficient chiral selector in the separation of racemic mixtures of drugs by capillary electrophoresis (CE). Results showed that 2-HB-beta-CD could provide higher separating capability than that of beta-CD and the similarly substituted 2-HP-beta-CD.     

Crystal structures of heptakis(2,6-di-O-ethyl)cyclomaltoheptaose

Heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (DE-beta-CD) was crystallized in two forms from hexane and 95% aqueous methanol, respectively: A form I crystal with the space group P2(1)2(1)2(1) and a form II crystal with the space group P3(1). In both crystals, DE-beta-CD molecules are in a round shape with intramolecular O-3-H...O-2 hydrogen bonds. In the form I crystal, the DE-beta-CD molecules are arranged along the twofold screw axis to form a helically extended polymeric chain by including the 6-O-ethyl groups of the adjacent molecule. One hexane molecule with twofold disorder is located in the intermolecular channel along the a-axis. In contrast, the DE-beta-CD molecules in the form II crystal form a helical arrangement along the threefold screw axis. One methanol and one water molecule are included on the O-6 side of the molecular cavity. The water molecule links the methanol molecule and two ethoxy groups of the adjacent DE-beta-CD molecule with hydrogen bonds. The result suggests the important role of solvent in the formation of helical arrangement of DE-beta-CD molecules.     

Isolation and structural analyses of positional isomers of 6(1),6(n)-di-O-(N-acetyl-beta-D-glucosaminyl)cyclomaltoheptaose (n=2, 3, and 4) and 6-O-[6-O-(N-acetyl-beta-D-glucosaminyl)-N-acetyl-beta-D-glucosaminyl]cyclomaltoheptaose.

6-O-[6-O-(N-acetyl-beta-D-glucosaminyl)-N-acetyl-beta-D-glucosaminyl]cyclomaltoheptaose (beta CD) and three positional isomers of 6(1),6(n)-di-O-(N-acetyl-beta-D-glucosaminyl)cyclomaltoheptaose (n=2, 3, and 4) in a mixture of products from beta CD and N-acetylglucosamine by the reversed reaction of beta-N-acetylhexosaminidase from jack bean were isolated and purified by HPLC. The structures of four isomers of di-N-acetylglucosaminyl-beta CDs were determined by FABMS and NMR spectroscopy. The degree of polymerization of the branched oligosaccharides produced by enzymatic degradation with bacterial saccharifying alpha-amylase (BSA) was established by LC-MS methods.     

Ionic complexation properties of per(3,6-anhydro)cyclodextrin derivatives towards lanthanides

Using per(3,6-anhydro)cyclodextrin derivatives [per(3,6-anhydro)CD], it was possible to produce new lanthanide chelates by careful choice of the size and functional groups. Heptakis(3,6-anhydro-2-O-methyl)cyclomaltoheptaose fulfils the best criteria for complexation of lanthanide ions. Nuclear magnetic resonance was used to derive the association constants and the stoichiometries of these new complexes. Finally, a three-dimensional structure of these complexes consistent with the NMR data is proposed, to ascertain the position of lanthanide in the cavity of the per(3,6-anhydro)CD. For the present purposes, heptakis(2-O-acetyl-3,6-anhydro)cyclomaltoheptaose, octakis(2-O-acetyl-3,6-anhydro)cyclomaltooctaose, heptakis(3,6-anhydro-2-O-methyl)cyclomaltoheptaose and octakis(3,6-anhydro-2-O-methyl)cyclomaltooctaose have been synthesized and purified.     

X-ray crystallography and solution NMR spectroscopy characterization of heptakis(2,3-di-O-acetyl-6-bromo-6-deoxy)cyclomaltoheptaose

Heptakis(2,3-di-O-acetyl-6-bromo-6-deoxy)cyclomaltoheptaose has been characterized in aqueous solution by 1D and 2D NMR spectroscopy and in the solid state by X-ray crystallography. In methanol solution, the acetyl groups were found to interact with both inward and outward-pointing protons. This and the strong deshielding of the bridging carbons, relative to the nonacetylated precursor, indicate macrocyclic flexibility. In the crystalline state the macrocycle exists as a methanol complex. It exhibits elliptical distortion, all glucose residues been tilted with their primary side toward the cavity. The existing strain due to the congestion of 14 acetyl groups at the secondary site is relieved by two glucose rings acquiring the rarely observed skew-boat conformation, (0)S(2), by the increased tilting of two glucose residues, as well as by minor variations of the torsion angles of the acetyl groups. The seven bromine atoms are quite accessible to nucleophiles.     

Structure of the complex of heptakis(2,6-di-O-methyl)-beta-cyclodextrin with (2,4-dichlorophenoxy)acetic acid

The structure of the complex formed by heptakis(2,6-di-O-methyl)-beta-cyclodextrin and (2,4-dichlorophenoxy)acetic acid was studied by X-ray diffraction. The dichlorophenyl moiety of the guest molecule was found outside the host hydrophobic cavity in the primary methoxy groups region whereas the oxyacetic acid chain penetrates the cavity from the primary face. The host molecules stacks along the a crystal axis forming a column. In the space between three successive hosts of the column, a guest molecule is accommodated.     

Synthesis and silica-based immobilization of monofunctionalized cyclomaltoheptaose derivatives for enantioselective HPLC

Heptakis(6-O-tert-butyldimethylsilyl-2,3-di-O-methyl)cyclomaltohep taose (6-TBDMS-2,3-Me-beta-CD) and heptakis(2,3,6-tri-O-methyl)cyclomaltoheptaose (per-Me-beta-CD) were monofunctionalized by introduction of a 5-cyanopentyl group attached to one of the O-2, O-3 or O-6 positions and subsequent reduction with lithium aluminum hydride to give the corresponding mono-O-(omega-aminohexyl) derivatives. Alternatively, after attachment of a 7-octenyl group and further epoxidation the corresponding mono-omega-epoxyoctyl derivatives of 6-TBDMS-2,3-Me-beta-CD were obtained. The mono-O-(omega-aminohexyl) derivatives were immobilized by reaction with glycidoxypropyl and 'aldehyde' silica, whereas aminopropyl silica was used for the immobilization of the monoepoxyoctyl derivatives. The immobilized cyclodextrin derivatives were partially evaluated as chiral stationary phases in high-performance liquid chromatography (HPLC) and micro-HPLC.     

Crystal structure of cyclomaltoheptaose (beta-cyclodextrin) complexes with p-aminobenzoic acid and o-aminobenzoic acid

Crystal structures of cyclomaltoheptaose (beta-cyclodextrin) complexes with p-aminobenzoic acid and o-aminobenzoic acid have been determined by single-crystal X-ray diffraction. The space group of the beta-cyclodextrin-p-aminobenzoic acid complex is P2(1) with a host:guest stoichiometry of 1:1, and that of the beta-cyclodextrin-o-aminobenzoic acid complex is P1 with a stoichiometry of 2:3. The different structures of the guest molecules lead to the different molecular packing structures of the two complexes. Intermolecular hydrogen-bond interactions are the main force that stabilize the supramolecular systems. In both crystals, there are water molecules located near the cavity rims and in interstices between molecules of beta-cyclodextrin participating in formation of intermolecular hydrogen bonds.     

Structure of inclusion complexes of cyclomaltoheptaose (cycloheptaamylose): crystal structure of the 1-adamantanemethanol adduct

Cyclomaltoheptaose (cycloheptaamylose) has been crystallized with 1-adamantanemethanol as the guest molecule. The complex crystallized in space group C222(1), with unit-cell dimensions a = 19.162 (13), b = 23.965 (17), and c = 32.597 (27) A. The structure was solved by rotation-translation search-methods. The cyclomaltoheptaose exists as a dimer in the crystal by means of extensive hydrogen-bonding across the secondary hydroxyl ends of two cyclomaltoheptaose molecules. The two halves of the dimer are related by a crystallographic two-fold axis. The primary hydroxyl ends of two adjacent cyclomaltoheptaose molecules are also related by a crystallographic two-fold axis, but do not directly hydrogen bond to one another. Instead, they are held in place by a strong hydrogen bond from the hydroxyl group of the 1-adamantanemethanol to a primary hydroxyl group on an adjacent cyclomaltoheptaose molecule. Other stabilizing hydrogen bonds are formed via three water molecules which are situated at the primary hydroxyl interface, and others that form parallel columns stabilizing the crystal structure. A unique feature of this complex is the presence of trapped water in the cavity at the secondary hydroxyl interface. This water is distributed over 3 disordered sites. Its presence blocks one possible site for the 1-adamantanemethanol, which, instead, binds near the primary hydroxyl end, with its hydroxyl group and part of the adamantane moiety protruding from the cyclomaltoheptaose.     

Regioselective sulfonylation at O-2 of cyclomaltoheptaose with 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole

2(I)-O-p-Tolylsulfonylcyclomaltoheptaose was obtained in 42% yield by reaction of 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole on NaH-deprotonated cyclomaltoheptaose in DMF and further converted into the corresponding mono-2(I),3(I)-manno-epoxide.     

Synthesis of novel cyclomaltoheptaose (beta-cyclodextrin) derivatives containing the Ebselen key moiety of benzoisoselenazolone

A series of five novel cyclomaltoheptaose (beta-cyclodextrin) derivatives containing benzoisoselenazolone groups have been synthesized as glutathione peroxidase mimics.     

Crystallographic analysis of the thermal motion of the inclusion complex of cyclomaltoheptaose (beta-cyclodextrin) with hexamethylenetetramine

The crystal structure of the inclusion complex of cyclomaltoheptaose (beta-cyclodextrin) with hexamethylenetetramine was determined at temperatures of 123, 173, 223, and 293 K. The rigid-body motion of the host and guest molecules was evaluated by means of the TLS method that represents the molecular motion in terms of translation, libration, and screw motion. In increasing the temperature from 123 to 293 K, the amplitude of the rigid body vibration of the host molecule was increased from 1.0 to 1.3 degrees in the rotational motion and from 0.16 to 0.17 A in the translational motion. The cyclomaltoheptaose molecule has the flexibility in seven alpha-(1-->4)-linkages, and each glucose unit was in the rotational vibration around an axis through two glycosidic oxygen atoms. As a result, the rigid-body parameters of cyclomaltoheptaose were considered to be overestimated because of including the contribution from the local motion of glucose units. In contrast, for the guest molecule having no structural flexibility, the TLS analysis demonstrated that the atomic thermal vibration was mostly derived from the rigid body motion. The rotational amplitude of hexamethylenetetramine was changed from 5.2 to 6.6 degrees in increasing the temperature from 123 to 293 K, while the change of the translational amplitude was from 0.20 to 0.23 A. The translational motion of the guest molecule was hindered by the inside wall of the host cavity. The molecular motion was characterized by the rotational vibration around the axis through two nitrogen atoms that were involved in the hydrogen-bond formation.     

Crystal structure of the inclusion complex of the antibacterial agent triclosan with cyclomaltoheptaose and NMR study of its molecular encapsulation in positively and negatively charged cyclomaltoheptaose derivatives

The inclusion complexes of triclosan with native cyclomaltoheptaose (beta-cyclodextrin, betaCD) as well as with negatively and positively charged derivatives are studied. The structure of the inclusion complex betaCD/triclosan in the crystalline state [P1, a=15.189(5), b=15.230(6), c=16.293(6), alpha=91.07(4), beta=91.05(3) gamma=100.71(3)] comprises two crystallographically independent host macrocycles A and B. The packing results in betaCD dimers that align head-to-head and form infinite channels along the c-axis. Only one guest molecule statistically disordered over two positions, (the dichlorophenyl ring in the cavities of either A or B) corresponds to each dimer (a 2:1 host/guest complex). The enclosed dichlorophenyl ring enters the dimer through the primary side, whereas the hydrophilic chlorophenol ring extends in the space between dimers. Water molecules in five positions are also enclosed in the intradimer region, arranged on a plane perpendicular to the sevenfold axis of betaCD. The NMR spectroscopic studies in aqueous solution show the presence of both 1:1 and 2:1 betaCD/triclosan complexes. In the first case, two different 1:1 complexes are simultaneously present, each with either ring entering the narrow primary side of one betaCD molecule. In the 2:1 complex both rings of triclosan are included in two independent betaCD hosts, a precursor to the supramolecular arrangement found in the crystalline form. In the case of the negatively charged sodium heptakis[6-deoxy-6-(3-thiopropionate)]-betaCD, the NMR studies at pH 7.9 show a complete inclusion of triclosan inside the host in two orientations, one for the non-ionized (phenol) and reverse for the ionized (phenolate) form. Finally, for the positively charged heptakis(6-aminoethylamino-6-deoxy)-betaCD, inclusion of triclosan is possible only when the pH is raised to 10 and it is concluded that both aromatic rings are alternatively inside the cavity. However in that case also, inclusion of the entire guest in the elongated cavity is suggested.     

The influence of cyclomaltooligosaccharides (cyclodextrins) on the enzymatic decomposition of l-phenylalanine catalyzed by phenylalanine ammonia-lyase

Cyclomaltohexaose (α-cyclodextrin) and cyclomaltoheptaose (β-cyclodextrin) as well as their four methyl ether derivatives, that is, hexakis(2,3-di-O-methyl)cyclomaltohexaose, hexakis(2,3,6-tri-O-methyl)cyclomaltohexaose, heptakis(2,3-di-O-methyl)cyclomaltoheptaose, and heptakis(2,3,6-tri-O-methyl)cyclomaltoheptaose were investigated as the additives in the course of enzymatic decomposition of l-phenylalanine catalyzed by phenylalanine ammonia-lyase. Only a few of those additives behaved like classical inhibitors of the enzymatic reaction under investigation because the values of the Michaelis constants that were obtained, as well as the maximum velocity values depended mostly atypically on the concentrations of those additives. In most cases cyclodextrins caused mixed inhibition, both competitive and noncompetitive, but they also acted as activators for selected concentrations. This atypical behaviour of cyclodextrins is caused by three different and independent effects. The inhibitory effect of cyclodextrins is connected with the decrease of substrate concentration and unfavourable influence on the flexibility of the enzyme molecules. On the other hand, the activating effect is connected with the decrease of product concentration (the product is an inhibitor of the enzymatic reaction under investigation). All these effects are caused by the ability of the cyclodextrins to form inclusion complexes.     

Monte Carlo docking simulations of cyclomaltoheptaose and dimethyl cyclomaltoheptaose with paclitaxel

The molecular basis for the remarkable enhancement of the solubility of paclitaxel by O-dimethylcyclomaltoheptaose (DM-beta-CD) over cyclomaltoheptaose (beta-cyclodextrin, beta-CD) was investigated with Monte Carlo docking-minimization simulation. As possible guests of inclusion complexation for the host cyclic oligosaccharides, two functional moieties of the suggested solution structure of paclitaxel were used where one is the C-3'N benzoyl moiety (B-ring) and the other is a hydrophobic (HP) cluster site among the C-3' phenyl (C-ring), C-2 benzoate (A-ring), and C-4 acetoxy moieties. The energetic preference of inclusion complexation of DM-beta-CD over beta-CD was analyzed on the basis of more efficient partitioning process of DM-beta-CD into the hydrophobic cluster site of the paclitaxel.