Γ-cyclodextrin Derivatives Research Articles

Host-Guest Complexation-Induced Aggregation Based on Pyrene-Modified Cyclodextrins for Improved Electronic Circular Dichroism and Circularly Polarized Luminescence.

Several γ-cyclodextrin (CD) derivatives mono- or di-substituted by pyrenes at the primary rim of the CD were demonstrated to aggregate into nano-strips in aqueous solutions, with the pyrene moieties interpenetrating into γ-CD cavities. The hydrophobic complexation-induced aggregation provides a rigid chiral environment for the pyrenes and leads to significant electronic circular dichroism (ECD) and circularly polarized luminescence (CPL) activities, giving unprecedently high gabs and glum values up to 4.3×10-2 and 5.3×10-2 , respectively. The aggregates lead to excimer emission with high quantum yields and show BCPL and BiCPL up to 338. 6 M-1 cm-1 and 169.3 M-1 cm-1 , respectively.

Facile synthesis of per(6-O-tert-butyldimethylsilyl)-α-, β-, and γ-cyclodextrin as protected intermediates for the functionalization of the secondary face of the macrocycles.

Per(6-O-tert-butyldimethylsilyl)-α-, β- and γ-cyclodextrin derivatives are well-known as synthetic intermediates that enable the selective mono-, partial, or perfunctionalization of the secondary face of the macrocycles. Although silylation of the primary rim is readily achieved by treatment with tert-butyldimethylsilyl chloride in the presence of pyridine (either alone or mixed with a co-solvent), the reaction typically results in a mixture containing both under- and oversilylated byproducts that are difficult to remove. To address this challenge in preparing a pure product in high yield, we describe an approach that centers on the addition of a controlled excess of silylating agent to avoid the presence of undersilylated species, followed by the removal of oversilylated species by column chromatography elution with carefully designed solvent mixtures. This methodology works well for 6-, 7-, and 8-member rings (α-, β-, and γ-cyclodextrins, respectively) and has enabled us to repeatedly prepare up to ⁓35 g of ≥98% pure product (as determined by HPLC) in 3 d. We also provide procedures for lower-scale reactions, as well as an example of how the β-cyclodextrin derivative can be used for functionalization of the secondary face of the molecule.

Isolation and biological evaluation of roseofungin and its cyclodextrin inclusion complexes

Roseofungin belongs to polyene antibiotics which is more active and less toxic comparing other polyenes of this group. Roseofungin was isolated from Actinomyces roseoflavus var. Roseofungini using different chro-matographic techniques and for the first time, the complexation of roseofungin with α-, β- and γ-cyclodextrin derivatives was performed. The binding patterns of the resulted complexes were studied in silico using mo-lecular docking techniques. The best binding mode was for roseofungin against γ-CD with an affinity value of ˗42.98 kcal/mol. The proposed binding mode of roseofungin against α-CD showed unusual interaction with an affinity value of ˗41.80 kcal/mol. Also, roseofungin bonded to β-CD with a binding affinity value of ˗35.03 kcal/mol. The antiradical and cytotoxic activities of roseofungin and its obtained α-, β- and γ-cyclo-dextrin complexes were determined. The antiradical activity was performed using butylhydroxyanisole as a reference, while the cytotoxic activity was determined using Artemia salina crustaceans. As a result of the biological activity study, it was found that roseofungin and some of its complexes have weak antiradical activities.

Enantioseparation of alanyl-phenylalanine analogs by capillary electrophoresis using negatively charged cyclodextrins as chiral selectors

The separation of the ll- and dd-enantiomers of the dipeptides Ala-Phe, Ala-phenylglycine (Phg), Ala-homoPhe, Ala-β-Phe, Gly-Phe and β-Ala-Phe was studied by capillary electrophoresis in the presence of negatively charged α-, β- and γ-cyclodextrin (CD) derivatives. Analysis was performed under standardized conditions in fused-silica capillaries at pH 2.5, 3.5 and 5.3. All analyte enantiomers could be separated at pH 2.5 under at least one of the experimental conditions. Especially β-CD derivatives proved to be effective chiral selectors. The enantiomer migration order depended on CD cavity size and substituent type, while peptide structure had only a minor effect. Upon increasing the pH from 2.5 to 5.3, reversal of the enantiomer migration order was observed frequently. Investigation of the apparent and, in the case of randomly substituted CDs, averaged complexation constants and mobilities of the diastereomeric peptide enantiomer-CD complexes indicated that in most cases the migration order in the presence of sulfated α-, β- and γ-CD and heptakis(6-O-sulfo)-β-CD could be explained by the stronger binding of the second migrating analyte by the CD at pH 2.5. However, in few cases the weaker bound enantiomer migrated second, which could be attributed to the higher mobility of the respective CD complexes. At pH 5.3, similar data were obtained for sulfated β-CD and heptakis(6-O-sulfo)-β-CD, i.e. the strength of the complexes determined the migration order for some peptides, while the migration sequence was based on the apparent (and averaged) mobility of the diastereomeric analyte-CD complexes in other cases.

PH-Controlled Chirality Inversion in Enantiodifferentiating Photocyclodimerization of 2-Antharacenecarboxylic Acid Mediated by γ-Cyclodextrin Derivatives.

Several γ-cyclodextrin (γ-CDx) derivatives were used as chiral hosts for the photocyclodimerization of 2-anthracenecarboxylic acid (AC). The effect of pH on photoreactivity and stereochemical outcome of photoproducts was investigated. Upon changing the solution pH, the stereochemical outcome of HH cyclodimer 3 was inverted from 25.2% to -64.4% and 41.2% to -76.2%, respectively, in the photocyclodimerization of AC mediated by bis-quinoline-modified γ-CDx 7 and its N-methylated derivative 8.

Supramolecular Assembly-Improved Triplet-Triplet Annihilation Upconversion in Aqueous Solution.

Water-soluble 9,10-diphenylanthracene-modified γ-cyclodextrin derivatives A1 and A2, in which the γ-cyclodextrin unit serves as a molecular host for a binding sensitizer, and the 9,10-diphenylanthracene moiety plays a role as an emitter/annihilator, were synthesized to investigate the supramolecular triplet-triplet annihilation (TTA) upconversion in aqueous solution. Both A1 and A2 readily aggregate and form nanoscale assemblies in water as a combined result of host-guest complexation and π-π stacking among the 9,10-diphenylanthracenes. The aggregation behavior of the supramolecular emitters was fully characterized by using a diversity of methods, including dynamic light scattering (DLS), SEM, NMR, fluorescence, and circular dichroism studies. Fluorescence spectroscopic analysis reveals that the emitters have high fluorescence quantum yields in water (82 and 90 % for A1 and A2, respectively), thus demonstrating that aggregation does not quench the fluorescence. By using a coordinated ruthenium sensitizer, a high TTA upconversion quantum yield of up to 6.9 % was observed for this supramolecular TTA system, which is significantly higher than the value (<0.5 %) obtained with nonassembled emitters in organic solvent and in contrast to the fact that TTA upconversion emission in aqueous solution is usually low or negligible. We ascribe the strong TTA upconversion emission in the present supramolecular assembly system to an efficient TTA process, which is facilitated along the stacked emitters by triplet energy migration and improved triplet-triplet energy transfer through host-guest complexation.

Assessment of the Physical Properties of Inclusion Complexes of Forchlorfenuron and γ-Cyclodextrin Derivatives and Their Promotion of Plant Growth.

The current study prepared solid dispersions of forchlorfenuron (CPPU) and γ-cyclodextrin (γCD) or CPPU and 2-hydroxypropyl-γ-cyclodextrin (HPγCD) via cogrinding and coprecipitation to assess their physicochemical properties and their effect on plant growth. According to phase solubility diagrams, both CPPU/γCD and CPPU/HPγCD formed an inclusion complex at a molar ratio of 1/1. According to differential scanning calorimetry and powder X-ray diffraction, a ground mixture (GM) of CPPU and γCD (molar ratio = 1/1), a GM of CPPU and HPγCD (molar ratio = 1/1), and a coprecipitate (CP) of CPPU and γCD (molar ratio = 1/1) formed an inclusion complex. According to 1H–1H nuclear Overhauser effect spectroscopy NMR spectroscopy of the GMs and CP, the aromatic rings of the CPPU molecule are presumably included in CD from the wider to the narrower rim of its ring. Cultivation of broccoli sprouts with the GMs and CP resulted in no differences in the length of sprouts in comparison to a commercial preparation (Fulmet).

Polyrotaxane Brushes Dynamically Formed at a Water/Elastomer Interface.

Dense polymer brushes with closely packed rotaxane structures were formed at the interface of water and a styrene-butadiene elastomer by spontaneous segregation of an amphiphilic polyrotaxane (PR), a mechanically interlocked polymer consisting of hydrophobic polybutadiene threading through multiple hydrophilic γ-cyclodextrin (γ-CD) derivatives. Segregation of PR at the water/elastomer interface was suggested by X-ray photoelectron spectroscopy. The polymer brush structure at the water interface was investigated using neutron reflectometry. Brush structures were found to depend on the number of CDs on the PRs; the PR with a small number of CDs formed a thinner and homogeneous brush, whereas the PR with a higher number of CDs formed a thicker and less-ordered brush. These PR-brushes showed protein repulsion, resulting from the surface-hydrated brush layer preventing direct contact of proteins.

Anionic cyclodextrins as versatile hosts for pharmaceutical nanotechnology: Synthesis, drug delivery, enantioselectivity, contrast agents for MRI

The review presents a full library of single-isomer primary rim per-carboxylate- and per-sulfate-α-, -β- and -γ-cyclodextrin (CD) derivatives and their potential for pharmaceutical nanotechnology. Recent advances in cyclodextrin chemistry have enabled robust methods for the synthesis of single-isomer anionic CDs. Numerous nanobio-applications have been already reported for these negatively charged derivatives, which alone or in combination with other biodegradable molecular platforms can become important carriers for targeted drug delivery and release. Specialized applications are also discussed, such as chiral separations, as well as the ability of per-6-carboxylated-cyclodextrins to coordinate with metal cations and especially with lanthanide cations that makes them candidates as contrast agents for Magnetic Resonance Imaging.

Betulin Complex in γ-Cyclodextrin Derivatives: Properties and Antineoplasic Activities in In Vitro and In Vivo Tumor Models

Given the present high incidence of melanoma and skin cancer, interest in potential drugs of plant origin has increased significantly. Pentacyclic lupane-type triterpenes are widely distributed in plants, offering numerous pharmacological benefits. Betulin is an important compound in the bark of Betula pendula Roth and has important therapeutic properties, including antitumor activities. Its biological effect is limited by its poor water solubility, which can be improved by cyclodextrin complexation. The best results have been obtained by using a novel cyclodextrin derivative, octakis-[6-deoxy-6-(2-sulfanyl ethanesulfonate)]-γ-CD. The complexes between betulin and the previously mentioned cyclodextrin were analyzed by scanning electron microscopy (SEM)and differential scanning calorimetry (DSC) and pharmacologically evaluated in vitro (MTT and immunocytochemistry tests) and in vivo in C57BL/6J mice. The solubility of betulin is improved by cyclodextrin complexation, which creates a stable complex that improves the in vitro and in vivo properties of the active compound.

Optical planar Bragg grating sensor for real-time detection of benzene, toluene and xylene in solvent vapour

We report on an optical planar Bragg grating sensor functionalized by a comparatively simple method to detect substances such as benzene, toluene and xylene (BTX). The functionalization is performed by allyl substituted γ-cyclodextrin derivatives which are immobilized on the sensor surface by dip coating. Our results prove the capability of this functionalized sensor system to detect lowest concentrations of BTX in solvent vapour in real-time with a sensitivity of 3±0.4 pm/100 ppm for benzene, 8±1 pm/100 ppm for toluene and 32±1 pm/100 ppm for m-xylene. Taking into account the spectral resolution and repeatability of the interrogation system this corresponds to a minimum concentration threshold of 200±25 ppm for benzene, 70±15 ppm for toluene and 20±2 ppm for m-xylene, respectively.

Determination of SDS Using Fluorescent &lt;i&gt;γ&lt;/i&gt;-Cyclodextrin Based on TICT in Aqueous Solution

Fluorescent γ-cyclodextrin derivatives, modified using N-phenyl-x-anthracenecarboxamido (ACs; x = 9, 1), were synthesized and investigated using fluorescence and UV-vis spectroscopy. Fluorescence enhancements of ACs were observed up to 12-fold by the addition of sodium dodecyl sulfate (SDS) below the critical micellar concentration (CMC). In the presence of a nonionic surfactant, such as Triton X-100, fluorescence spectra were scarcely changed. The fluorescence selectivity between SDS and Triton X-100 was clarified from the different spectral behaviors by circular dichroism and (1)H NMR spectroscopies.

Symmetry Requirements for Effective Blocking of Pore-Forming Toxins: Comparative Study with α-, β-, and γ-Cyclodextrin Derivatives

We compared the abilities of structurally related cationic cyclodextrins to inhibit Bacillus anthracis lethal toxin and Staphylococcus aureus α-hemolysin. We found that both β- and γ-cyclodextrin derivatives effectively inhibited anthrax toxin action by blocking the transmembrane oligomeric pores formed by the protective antigen (PA) subunit of the toxin, whereas α-cyclodextrins were ineffective. In contrast, α-hemolysin was selectively blocked only by β-cyclodextrin derivatives, demonstrating that both symmetry and size of the inhibitor and the pore are important.

Supramolecular FRET photocyclodimerization of anthracenecarboxylate with naphthalene-capped γ-cyclodextrin

γ-Cyclodextrin (CD) derivatives with a naphthalene moiety anchored to one or two of the glucose units of the CD were synthesized in order to investigate the effects of flexible and rigid capping upon complexation, as well as Förster resonance energy transfer (FRET) and photochirogenic behavior of anthracenecarboxylate (AC) moieties. UV–vis, circular dichroism and fluorescence spectral studies revealed that two AC molecules are simultaneously included in the modified γ-CD cavity to form a right-handed screw and also that the naphthalene cap efficiently transfers the singlet energy to AC included in the CD cavity via the FRET mechanism. Compared to native γ-CD, the modified γ-CDs showed much higher first association constants (K1) but relatively lower second association constants (K2) for AC, leading to two-fold larger overall affinities (K1K2). Photocyclodimerization of AC with these modified γ-CDs produced more head-to-head (HH) dimers in much better enantiomeric excesses (ee) for anti-HH dimer compared to native γ-CD. Interestingly, FRET excitation further enhanced the chemical and optical yields of anti-HH dimer up to 36% and 35% ee, for which the highly efficient FRET sensitization within the CD cavity, minimizing the “contamination” from the achiral “outside” photoreaction, is responsible. FRET sensitization also enabled us to achieve the catalytic photocyclodimerization of AC with a sub-equivalent amount of chiral supramolecular host.

Sulfobutyl ether-alkyl ether mixed cyclodextrin derivatives with enhanced inclusion ability

The aim of this work was to study the complexation capability of new sulfobutyl ether-alkyl ether (SBE-AE-CD) mixed β- and γ-cyclodextrin derivatives with a series of structurally related steroids (6α-methylprednisolone, prednisolone, triamcinolone, D(−) norgestrel and hydrocortisone) and a number of dihydropyridine calcium channel blockers (nimodipine, nitrendipine, nifedipine) that traditionally interact poorly with other cyclodextrins (CDs). The effect of the total degree of substitution (TDS) and of the length of the alkyl side chain on binding capacity of these new modified CDs was evaluated as was their ability to induce red blood cell hemolysis. An attempt was made to correlate hemolysis to surface activity. Binding constants between the SBE-AE-CDs and selected molecules were determined by spectroscopic studies, and only in few cases by solubility studies. Hemolysis percentage was determined using citrated rabbit blood and citrated human blood with UV analysis. The surface activity was measured with a tensiometer. A significant improvement in the binding capacity between various substrates and the new SBE-AE-CDs was observed when compared to the SBE-CDs. The length of the alkyl chain and total degree of alkylation affected the binding with the relationship being complex. For most compounds, an intermediate degree of substitution appeared to be advantageous. The hemolysis studies showed that some of the derivatives may induce hemolysis and this correlated with higher surface activity for some but not all of the derivatives. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4769–4780, 2009

Refractive -index changes of thin films of photo-reactive α-, β-, and γ-cyclodextrin derivatives upon photo-irradiation

We have synthesized cyclodextrin (CD) derivatives with pendant norbornadiene (CD-NBD), with pendant azobenzene (CD-AZ), with pendant cinnamate (CD-CI), with pendant chalcone (CD-CH), and with pendant anthracene (CD-AT). In thin films of these CD derivatives under UV irradiation, photochemical isomerization of CD-NBD and CD-AZ, and photochemical dimerization of CD-CI, CD-CH, and CD-AT proceeded smoothly. The photochemical reactions were accompanied with large refractive index changes (Δ n D's) of 0.023–0.030 (CD-NBD), 0.015–0.023 (CD-AZ), 0.041–0.048 (CD-CI), 0.057–0.071 (CD-CH), and 0.062–0.083 (CD-AT), as determined by ellipsometry.

Carboxymethylated cyclodextrins and their paramagnetic lanthanide complexes as water-soluble chiral NMR solvating agents

Cyclodextrins that are indiscriminately carboxymethylated at the 2-, 3-, and 6-position are used as chiral NMR solvating agents for cationic aromatic amines and aromatic hydroxy amines. Enantiomeric discrimination with the α-, β-, and γ-cyclodextrin derivatives is compared. The carboxymethylated derivatives are consistently more effective as chiral NMR discriminating agents for cationic substrates than native cyclodextrins. The most effective cyclodextrin varies for different substrates, although the β-cyclodextrin derivative is usually the best for the phenyl-containing compounds examined herein. Addition of paramagnetic praseodymium(III) or ytterbium(III) to mixtures of the carboxymethylated cyclodextrin and substrate often causes enhancements in enantiomeric discrimination and facilitates measurements of enantiomeric purity. The lanthanide ion bonds to the carboxymethyl groups and shifts the NMR spectra of substrate molecules in the cyclodextrin cavity.

Effect of alkylcarbonates of γ-cyclodextrins with different chain lengths on drug complexation and release characteristics

Alkylcarbonates of γ-cyclodextrins were produced and their inclusion complexes with four poorly water-soluble drugs of different structures and solubilities were prepared. The alkylcarbonates and the alkylcarbonate drug complexes were characterized by DSC and XRPD; the physical mixtures were used as control. Solubility capacities were evaluated by phase solubility studies. The effect of alkyl chain length on the complexation and release behaviour was investigated as well. The XRPD patterns of alkylcarbonates showed that the derivatives lose the original crystallinity of γ-cyclodextrins. The series of alkylcarbonates formed inclusion complexes with the drugs considered. Both XRPD and DSC analyses did not show neither the reflections of the crystalline structures nor the melting peaks of the drugs, respectively. These γ-cyclodextrin derivatives can improve drug solubility and influence the drug release rates while the alkyl chain length may affect these properties.

Effect of akyl-γ-cyclodextrins on the stability of retinol

Inclusion complexation between retinol (RET) and two synthetic alkyl carbonates of γ-cyclodextrin (alkyl-γ-CD) derivatives, ethyl-γ-cyclodextrin (E-CD) and octyl-γ-cyclodextrin (O-CD), was investigated by means of different techniques. The complexes were characterized by differential scanning calorimetry (DSC). Phase solubility studies, according to the method of Higuchi and Connors [1] were used to evaluate the complexation in aqueous solution at room temperature. In the present study inclusion complexes of retinol with E-CD and with O-CD were prepared to prevent its rapid degradation. In order to investigate the behavior of retinol under UV light, test of irradiation was performed separately on samples prepared dispersing retinol (0.1% w/w) or an equivalent amount of retinol/alkyl-γ-CD respectively in hydroxyethylcellulose (HEC) gel and in an O/W emulsion. The stability over time of retinol was also investigated storing the samples at 40 °C. Moreover retinol permeation through porcine skin has been evaluated employing Franz cells [2]. Retinol solubility was increased in presence of cyclodextrins while DSC analysis suggest that this inclusion agents are able to interact with retinol. Data for skin accumulation in porcine ear skin showed that alkyl-CDs increase of approximatively 1,5-fold retinol skin accumulation. Studies on the stability showed that both the inclusion complexes considered are able to increase retinol stability to light exposure and also to heat.

Complexation of the sunscreen agent, 4-methylbenzylidene camphor with cyclodextrins: Effect on photostability and human stratum corneum penetration

The interaction between the sunscreen agent, 4-methylbenzylidene camphor (4-MBC) and hydrophilic α-, β- and γ-cyclodextrin derivatives was investigated in water by phase-solubility analysis. Among the studied cyclodextrins, random methyl-β-cyclodextrin (RM-β-CD) had the greatest solubilizing activity. The complexation of the sunscreen agent with RM-β-CD was confirmed by nuclear magnetic resonance spectroscopy and powder X-ray diffractometry. The light-induced decomposition of 4-MBC in emulsion vehicles was markedly decreased by complexation with RM-β-CD (the extent of degradation, determined by HPLC, was 7.1% for the complex compared to 21.1% for free 4-MBC). The influence of RM-β-CD on the human skin penetration of the sunscreen was investigated in vivo using the tape stripping method, a useful procedure for selectively removing the outermost cutaneous layers. Considerable quantities (21.2–25.1% of the applied dose) of 4-MBC permeated in the stratum corneum. However, no significant differences in the amounts of UV filter in the 10 first strips of the horny layer were observed between the formulations containing 4-MBC free or complexed with RM-β-CD. Therefore, RM-β-CD complexation did not alter the retention of 4-MBC in the superficial layers of the stratum corneum, where its action is more desirable.