Cyclodextrin Ring Research Articles

Evaluation of a liquid chromatography method for quality control of methylated cyclodextrins

Halo C18 column (fused core particles) and Chromolith RP18 column (monolith) were evaluated in liquid chromatography in order to analyze methylated-β-cyclodextrins (Me-β-CD) with various degrees of substitution, DS such as the number of methyl groups per cyclodextrin ring. Chromolith RP18 enables a performing analysis of Me-β-CD with low DS but is not suitable for dimethyl-β-cyclodextrins (DM-β-CD). On the other hand, Halo C18 column allows an improved fingerprint of CDs having a DS from 4.9 up to a value major than 14 and avoiding the use of various chromatographic systems. Thus, liquid chromatography performed with this column and an evaporative light scattering detector can be used as a generic system for methylated CD analysis. Moreover, fused core particles of Halo C18 column enables a rapid analysis and liquid chromatography coupled with electrospray-mass spectrometry appears as a powerful tool to determine co-elution and to characterize various isomers of complex methylated-β-cyclodextrin mixtures.

Host–Guest Complex of β-Cyclodextrin and Disulfide Form of 4-Aminothiophenol

An inclusion complex of β-cyclodextrin and 4-aminothiophenol was assembled by hydrophobic interaction of the host (β-cyclodextrin) and guest (4-aminothiophenol). The complex was isolated as crystalline solid and studied by single crystal X-ray diffraction method along with NMR and IR spectroscopy. Two cyclodextrin rings each containing one disulfide form of 4-aminothiophenol were found to pair up by hydrogen bonding of the outer rim -OH groups. The phenyl disulfide moiety of 4-aminophenyl disulfide molecule was found in the core of β-cyclodextrin, while the amino functional groups were positioned to the exterior of the cyclodextrin ring. Phenyl rings of the guest molecule from each partner of the paired cyclodextrin complex were found parallel to each other, indicating possible π-π stacking interaction between them.

Detoxification of tabun at physiological pH mediated by substituted β-cyclodextrin and glucose derivatives containing oxime groups

The ability of 13 β-cyclodextrin and 2 glucose derivatives containing substituents with oxime groups as nucleophilic components to accelerate the degradation of tabun at physiological pH has been evaluated. To this end, a qualitative and a quantitative enzymatic assay as well as a highly sensitive enantioselective GC–MS assay were used. In addition, an assay was developed that provided information about the mode of action of the investigated compounds. The results show that attachment of pyridinium-derived substituents with an aldoxime group in 3- or 4-position to a β-cyclodextrin ring affords active compounds mediating tabun degradation. Activities differ depending on the structure, the number, and the position of the substituent on the ring. Highest activity was observed for a β-cyclodextrin containing a 4-formylpyridinium oxime residue in 6-position of one glucose subunit, which detoxifies tabun with a half-time of 10.2min. Comparison of the activity of this compound with that of an analog in which the cyclodextrin ring was replaced by a glucose residue demonstrated that the cyclodextrin is not necessary for activity but certainly beneficial. Finally, the results provide evidence that the mode of action of the cyclodextrin involves covalent modification of its oxime group rendering the scavenger inactive after reaction with the first tabun molecule.

Cyclodextrin functionalization: Simple routes to tailored solubilities and nanoscopic polymer networks

AbstractThe systematic chemical modification of cyclodextrins (CDs) provides an opportunity to create new substances with novel phase transfer, guest–host, solubility, and network properties. Such materials have several potential applications in polymer science, including free‐volume modifiers, stabilizers or compatibilizers, and scaffolds or templates for synthesizing new materials. In this study, we describe simple, inexpensive, and easy purification one‐pot methods to selectively functionalize CD rings with short‐ and long‐chain alkyl derivatives of varying polarity. Using bifunctional reagents in the same reaction scheme yields CD‐based polymer networks. Particular attention is devoted to solution and solid‐state NMR experiments that reveal the type and extent of functionalization, which may be used to control solubility and swelling. Alkyl chain functionalization may be expressed as the average number of CH2 units attached per CD ring, the magnitude of which can reach at least 16 and the product still be water soluble, but products become insoluble in water at a value of 32. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent

The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native β-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (−)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents.

Synthesis of a “molecular rope curtain”: Preparation and characterization of a sliding graft copolymer with grafted poly(ethylene glycol) side chains by the “grafting onto” strategy

AbstractA sliding graft copolymer (SGC) with poly(ethylene glycol) (PEG) side chains was prepared by ester formation between terminal carboxyl groups of oxidized PEG methyl ether with molecular weight of 2000 (mPEG2000‐COOH) and hydroxyl groups of a polyrotaxane consisting of PEG and cyclodextrins (CDs). Formation of the SGC structure was confirmed by 1H NMR, attenuated total reflectance Fourier‐transformed infrared, and gel permeation chromatography. The SGC was soluble in good solvents of PEG and insoluble in poor solvents of PEG. Estimation of the number of grafted mPEG chains suggested a “rope‐curtain” like structure, in which an mPEG chain is connected to each CD ring. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011

Synthesis of new hybrid nanomaterials: promising systems for cancer therapy

Polyrotaxanes consisting of cyclodextrin rings, polyethylene glycol axes and quantum dot (QD) stoppers were synthesized and characterized. The molecular self-assembly of polyrotaxanes led to spindlelike nano-objects whose shape, size and position were dominated by QD stoppers. Due to their well-defined molecular self-assemblies, carbohydrate backbone, high functionality and several types of functional groups together with the high luminescence yield, synthesized hybrid nanostructures were recognized as promising candidates for biomedical applications. The potential applications of the molecular self-assemblies as drug-delivery systems was investigated by conjugation of doxorubicin (DOX) to their functional groups and then release the drug inside the cancer cells in mouse tissue connective fibroblast adhesive cell line L929. It was found that the molecular self-assemblies quickly transfer through the cell membrane and slowly release the drug into the intracellular environment. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell cycle assays showed that the molecular self-assemblies degrade back into individual molecules that can be broken down by the cell metabolically, confirming that they can be used as new drug-delivery systems with high treatment efficacy and minimum side effects for future cancer therapy, thus forming a firm foundation for further study and improvement. From the Clinical EditorThis study investigates polyrotaxanes consisting of cyclodextrin rings, polyethylene glycol axes and quantum dot (QD) stoppers as promising candidates for biomedical applications, including cancer therapy.

Polyrotaxane/gold nanoparticle hybrid nanomaterials as anticancer drug delivery systems

Gold nanoparticles (Au NPs) have been widely used in various biomedical applications, including photothermal therapy, imaging and drug delivery. This study deals with the synthesis of new hybrid nanostructure-based drug delivery systems (DDSs), consisting of Au NP cores and polyrotaxane shells (Au NPs@PR). In order to prepare the polyrotaxanes (PRs), cyclodextrin rings were threaded onto poly(ethyleneglycol) (PEG) axes and, then, the pseudopolyrotaxanes were capped by Au NPs. The electrostatic interactions between the Au NPs and the polyrotaxane backbone led to the Au NPs@PR hybrid nanomaterials. Anticancer drugs, such as cisplatin (diamminedichloroplatinum, CDDP) and doxorubicin (DOX) were conjugated to Au NPs@PRs and their controlled release, through the photothermal properties of the Au NP cores, was investigated. To prove the efficacy of the DDSs, they were endocytosed by cancer cells (mouse tissue connective fibroblast adhesive cell line, L929) and the anticancer drugs were released by a photothermal explosion of the Au NPs@PR hybrid nanomaterials. It was found that these systems are able to release drugs and kill cancer cells controllably.

Macroscopic self-assembly through molecular recognition

Molecular recognition plays an important role in nature, with perhaps the best known example being the complementarity exhibited by pairs of nucleobases in DNA. Studies of self-assembling and self-organizing systems based on molecular recognition are often performed at the molecular level, however, and any macroscopic implications of these processes are usually far removed from the specific molecular interactions. Here, we demonstrate that well-defined molecular-recognition events can be used to direct the assembly of macroscopic objects into larger aggregated structures. Acrylamide-based gels functionalized with either host (cyclodextrin) rings or small hydrocarbon-group guest moieties were synthesized. Pieces of host and guest gels are shown to adhere to one another through the mutual molecular recognition of the cyclodextrins and hydrocarbon groups on their surfaces. By changing the size and shape of the host and guest units, different gels can be selectively assembled and sorted into distinct macroscopic structures that are on the order of millimetres to centimetres in size.

Acetylated Cyclodextrins as New Organogelators

Abstract Acetylated cyclodextrins (CDs), including peracetylated α- and β-CDs as well as 2,3-O-diacetylated α- and β-CDs, were found to function as organogelators for organic solvents such as benzene, toluene, and xylenes at ambient temperature. Their organogelation capability was strongly affected by both the CD ring size and the degree of acetylation. Peracetylated α-CD showed the highest organogelation capability among these acetylated CDs, possibly due to the effective construction of three-dimensional networks by the pillar-like assemblies in the organic solvents.

Synthesis and Characterization of Polyrotaxane−Amino Acid Conjugates: A New Synthetic Pathway for Amino-Functionalized Polyrotaxanes

Novel polyrotaxane conjugates possessing side chains of protected amino acids, that is, N(α)-tert-butyloxycarbonylglycine (Boc-Gly) and N(α)-benzyloxycarbonylglycine (Z-Gly), were successfully prepared via the carbonyldiimidazole-mediated esterification of hydroxyl groups in a polyrotaxane. The prepared conjugates were soluble in a wide variety of organic solvents, including N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, pyridine, and methanol. Thermogravimetric measurements of the conjugates showed three-step decomposition curves corresponding to the decompositions of the amino acid, poly(ethylene glycol) axis, and cyclodextrin rings. The Z-Gly-polyrotaxane conjugate showed a remarkable exotherm at 334 °C, together with a large weight loss. Treatment of the Boc-Gly-polyrotaxane conjugate with neat trifluoroacetic acid resulted in the complete removal of the Boc groups and gave a cationic polyrotaxane with many free primary amino groups, the amount of which was determined by colloidal titrations.

Face selective translation of a cyclodextrin ring along an axle

A cyclodextrin ring was face-selectively transferred between two stations linked by a 2-methylpyridinium group on an axle molecule.

Electrospinning of Cyclodextrin–Pseudopolyrotaxane Nanofibers

Cyclodextrins (CDs) are distinctive molecules that can form noncovalent host–guest complexes with a variety of molecules to yield intriguing supramolecular structures. Electrospinning has gained enormous attention since this versatile technique enables production of multifunctional nanofibers made from various polymers, polymer blends, composites, and ceramics. Electrospun nanofibers containing cyclodextrin inclusion complexes are particularly attractive because of the unique properties obtained by combining the large surface area of a polymer nanofiber carrier with the specific chemical structure of the CD complex. Herein we report the first results from electrospinning cyclodextrin inclusion complexes and/or cyclodextrin pseudopolyrotaxanes. Cyclodextrins are cyclic oligosaccharides with a toroidshaped molecular structure consisting of a(1,4)-linked glucopyranose units (Figure 1a). The most common natural CDs have either six, seven, or eight glucopyranose units and are referred to as a-, b-, and g-cyclodextrins, respectively (Figure 1b). The hydrophobic cavity of CDs allows them to form host–guest complexes with various small molecules and macromolecules. The stability of CD complexes depends on many factors such as the size or shape match between host and guest, chemical environment, and the binding forces (e.g., hydrophobic interactions, van der Waals attractions, hydrogen bonding, and electrostatic interactions) between the host CD and guest molecules. Since the physical and chemical properties of incorporated guest compounds can be tailored by CD complexation, CDs are used in a variety of application areas, such as pharmaceuticals (e.g., enhancement of drug solubility and stability, bioavailability, controlled drug delivery, and reduction of drug toxicity), 15] functional food additives (stabilization of volatile or unstable flavors and masking or removal of unwanted tastes and odor), cosmetics and home or personal care (releasing fragrances and masking unpleasant odors), and textiles (stabilization and controlled release of textile additives). CD pseudopolyrotaxanes, formed by threading a polymer chain or long molecule through many CD rings, have fascinating supramolecular structures with unusual properties. It has been shown that CD pseudopolyrotaxanes can be formed with various synthetic polymers, biopolymers, conducting polymers, dyes, polypeptides, proteins, and enzymes, and that the huge variety of supramolecular structures are extremely useful in many diverse areas. The nanostructure or microstructure and the functionality of the guest molecules are altered when encapsulated by CD molecules; furthermore, CD rings assist the stabilization and protection of the guest molecules and can control or sustain their delivery. CDs are natural, nontoxic, and slowly biodegradable, and consequently CD polyrotaxanes are very attractive candidates for smart materials, controlled or sustained delivery systems, sensor devices, molecular switches, or other diagnostic systems. Electrospinning is as a versatile and cost-effective technique for producing multifunctional nanofibers. Nanofibers and their mats have several remarkable characteristics such as large surface area to volume ratios, pore sizes in the nanometer range, unique physical and mechanical properties, and the chemical, physical, and functional properties of the nanofiber surfaces are fairly easy to modify. It has been shown that the very interesting properties and the multifunctionality of the nanofibers make them favorable candidates for use in many areas including biotechnology (tissue engineering, controlled or sustained release systems), textiles (delivery and stabilization of additives) and membranes/filters. The incorporation of CD-pseudopolyrotaxanes into nanofibers is extremely interesting since such the resulting CDcomplex-containing nanowebs will have unique characterFigure 1. a) Chemical structure of a-CD; b) approximate dimensions of g-, b-, and a-CDs; schematic representation of packing structures of c) cage-type and d) channel-type a-CD crystals.

Tuning Intrachain versus Interchain Photophysics via Control of the Threading Ratio of Conjugated Polyrotaxanes

Effective nanoscale control of intermolecular interactions in conjugated polymers is needed for the optimal development and exploitation of the latter in low-cost, large-area consumer electronics items, such as light-emitting and photovoltaic diodes, or transistors. Here we report our investigations on insulated molecular wires constituted by conjugated polymers threaded into cyclodextrin rings. Until now, there has been no detailed quantitative understanding of the role of progressive cyclodextrin encapsulation (quantifiable by the so-called "threading ratio", TR, or number of cyclodextrins per repeat unit) in tailoring the photophysics of the conjugated polymeric wires. We combine spectroscopic, electrical and surface analysis techniques to elucidate how the TR of cyclodextrin-threaded molecular wires controls formation of interchain species and related physical properties (0 < TR < or = 2.3; the maximum theoretical TR for close-packed CDs is 2.8). Increasing TR enhances the solid-state photoluminescence (PL) and electroluminescence quantum efficiency. To unravel the effect of progressive encapsulation on the intrachain decay kinetics of the polymer backbone, we added an electron-accepting quenching agent, methyl viologen (MV), to the polymer solutions. MV predominantly quenches the aggregate PL, thus enabling measurement of the decay kinetics of the intrinsic exciton even for low-TR polyrotaxanes, for which the different contributions are otherwise difficult to disentangle.

Copolymer−Cyclodextrin Inclusion Complexes in Water and in the Solid State. A Physico-Chemical Study

The formation of inclusion complexes (ICs) composed of cyclodextrins (CDs) and poly(ethylene oxides)-poly(propylene oxides)-poly(ethylene oxides) (PEO-PPO-PEO) was studied. To this purpose, native and hydroxypropyl cyclodextrins with different cavity size were chosen. The PEO-PPO-PEO copolymers were selected to study the role of the molecular weight, keeping constant the hydrophilic/hydrophobic ratio, and the hydrophilicity. The volumetric studies at 25 degrees C allowed to determine the equilibrium constant and the volume change for the IC formation in water as well as the IC stoichiometry. Surface tension experiments evidenced that the copolymer and the CD interfacial behavior is controlled by the formation of ICs taking place in the bulk phase. It was proved that the differential scanning calorimetry (DSC) is a valid method to describe quantitatively the IC in the solid state. The combination of volumes, DSC and FTIR techniques together with the geometric information highlighted the following points: (1) the included copolymer is in the amorphous state; (2) the IC composed of native CDs adopts a channel structure with two EO units incorporated into one CD molecule; (3) the IC composed of hydroxypropyl-cyclodextrin is a polymeric structure like a necklace decorated with CD rings. Finally, TGA experiments showed that the thermal stability of the IC depends on the nature of both components.

Synthesis of cationic β-cyclodextrin derivatives and their applications as chiral stationary phases for high-performance liquid chromatography and supercritical fluid chromatography

Four cationic β-cyclodextrin derivatives, namely mono-6-(3-methylimidazolium)-6-deoxy-perphenylcarbamoyl-β-cyclodextrin chloride (MPCCD), mono-6-(3-methylimidazolium)-6-deoxyper(3,5-dimethylphenylcarbamoyl)-β-cyclodextrin chloride (MDPCCD), mono-6-(3-octylimidazolium)-6-deoxyperphenylcarbamoyl-β-cyclodextrin chloride (OPCCD) and mono-6-(3-octylimidazolium)-6-deoxyper(3,5-dimethylphenylcarbamoyl)-β-cyclodextrin chloride (ODPCCD), have been synthesized and physically coated onto porous spherical silica gel to obtain novel chiral stationary phases (CSPs). The performances of these CSPs are studied on high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) using 18 racemic aryl alcohols as test analytes. Among these four CSPs, OPCCD shows the best separation results for all analytes on both HPLC and SFC analyses. Chromatographic studies reveal that the CSPs consisting of an n-octyl group on the imidazolium moiety and phenylcarbamoyl groups on the cyclodextrin ring provide enhancement of analyte–chiral substrate interactions over CSPs bearing the methyl group on the imidazolium moiety and 3,5-dimethylphenylcarbamoyl groups on the cyclodextrin ring.

Supramolecular Gels Based on Multi‐Walled Carbon Nanotubes Bearing Covalently Attached Cyclodextrin and Water‐Soluble Guest Polymers

AbstractThe preparation of associative networks containing multi‐walled carbon nanotubes (MWCNTs) with covalently attached cyclodextrin (CD) rings and poly[(isobutylene)‐co‐(maleic anhydride)‐co‐(maleic acid‐(4‐tert‐butylphenyl)amide)] in water is described in this study. The synthesis of CD containing MWCNTs is realized by an amidation reaction of oxidized MWCNTs with propargylamine followed by a 1,3‐dipolar cycloaddition with CD‐azide. Dispersion behavior indicated the high stability of these networks. An increase in viscosity compared to a solution of pure polymer as a cause of network formation is observed. The addition of a CD‐decomposing enzyme (taka‐diastase from Aspergillus oryzae) let the network collapse and results in sedimentation of the modified MWCNTs.magnified image

Supramolecular Controlled Pseudo-LCST Effects of Cyclodextrin-Complexed Poly(ionic liquids)

We investigated the complexation of monomeric 1-butyl-3-vinylimidazolium bis(trifluoromethylsulfonyl)imide ([bvim][Tf2N]) with different cyclodextrins (CDs) in water. Furthermore, we discovered that the poly([bvim][Tf2N]) 1 showed a pseudo-LCST (lower critical solution temperature) effect in the presence of CD. It was shown that the CD ring complexates only the polymer anion and slips off at higher temperature where the poly(ionic liquid) becomes insoluble in water. We were encouraged to prove this effect by turbidity measurements, microcalorimetric titrations, dynamic light scattering, and enzymatic scission of the CD.

Photochemical molecular imprinting of cholesterol

Cinnamoylated photocrosslinkable cyclodextrin derivatives (BCC) were synthesized by the substitution of β-cyclodextrin (β-CD) with cinnamoyl chloride (CC) and crosslinked with either hexamethylenediisocyanate (HMDI) or toluenediisocyanate (TDI). Cyclodextrin rings were substituted with one or two cinnamoyl moieties, as found from mass spectrometry. The polymeric matrix with cholesterol molecular imprint was obtained on irradiation of molecular assembly formed by the cinnamoyl-functionalized β-cyclodextrin-cholesterol with light at 275 nm, absorbed exclusively by the cinnamoyl chromophores. Irradiation induced crosslinking due to the photodimerization of the cinnamoyl moieties. To determine the adsorption properties of the produced material imprinting was performed in the presence of tritiated cholesterol and the intensity of β radiation from the material was measured. The materials obtained by the adsorption of tritiated cholesterol by nonirradiated polymer were used as controls. It was found that the polymer photocrosslinked in the presence of cholesterol have shown a considerable higher adsorption capacity for cholesterol than the control materials. This confirmed successful formation of molecularly imprinted polymer (MIP) by photochemical crosslinking. The selectivity of imprinting was also confirmed using compounds of similar structures, i.e. ergosterol, dehydroergosterol, and Vitamin D.

Preparation of a "sliding graft copolymer", an organic solvent-soluble polyrotaxane containing mobile side chains, and its application for a crosslinked elastomeric supramolecular film.

A novel "sliding graft copolymer" (SGC), in which many linear poly-ε-caprolactone (PCL) side chains are bound to cyclodextrin rings of a polyrotaxane, was prepared by ring-opening polymerization of ε-caprolactone initiated by hydroxyl groups of the polyrotaxane. An amorphous, flexible, and sufficiently tough elastomer film was prepared by crosslinking the obtained SGC-a supramolecule possessing a number of mobile side chains-with hexamethylene diisocyanate (HMDI).