Cyclodextrin Ring Research Articles

Chlorpropamide-cyclodextrin inclusion complexes, theoretical basis of stability

A study of the stability of inclusion complexes of chlorpropamide and α, β, γ, and HP-β cyclodextrin, has been carried out using molecular dynamics simulations. The contribution of weak interactions to the stability of the complexes through DFT has been analyzed. The conventional molecular dynamics analysis suggests stable complexes for the inclusion of chlorpropamide. As expected, the complex stabilization is driven by hydrophobic interactions between cyclodextrin and chlorpropamide aromatic ring; similar mobility of chlorpropamide in the cyclodextrin cavities was observed. Molecular dynamics results indicate that intermolecular hydrogen bonds appeared between 17.70 and 22.52 % of the simulation time; consequently, the crucial complex stabilizing interactions encompass more than just hydrogen bonds, revealing a more intricate network of stabilizing forces at play. For the first time, based on quantum chemistry, a correlation between the electron density contributions to weak interactions and the glucopyranose units in each CD is presented. The most relevant stabilizing interactions are of the van der Waals type, followed by small contributions from hydrogen bonds. Non-covalent interactions are more intense in the chlorpropamide/HP-β cyclodextrin complex than in other systems. The inclusion complexes formed with β-type cyclodextrins are the most stable (due to the number and intensity of the contributions), in agreement with the molecular dynamics simulation results. In addition, MMPBSA and QM energies predict CPD/αCD as unstable and least stable complex, respectively. These results highlight the importance of β-type cyclodextrins in the formation of creating reliable inclusion complexes, which could be potentially applied to molecular encapsulation and drug delivery systems.

Highly Stretchable Stress-Strain Sensor from Elastomer Nanocomposites with Movable Cross-links and Ketjenblack.

Practical applications like very thin stress-strain sensors require high strength, stretchability, and conductivity, simultaneously. One of the approaches is improving the toughness of the stress-strain sensing materials. Polymeric materials with movable cross-links in which the polymer chain penetrates the cavity of cyclodextrin (CD) demonstrate enhanced strength and stretchability, simultaneously. We designed two approaches that utilize elastomer nanocomposites with movable cross-links and carbon filler (ketjenblack, KB). One approach is mixing SC (a single movable cross-network material), a linear polymer (poly(ethyl acrylate), PEA), and KB to obtain their composite. The electrical resistance increases proportionally with tensile strain, leading to the application of this composite as a stress-strain sensor. The responses of this material are stable for over 100 loading and unloading cycles. The other approach is a composite made with KB and a movable cross-network elastomer for knitting dissimilar polymers (KP), where movable cross-links connect the CD-modified polystyrene (PSCD) and PEA. The obtained composite acts as a highly sensitive stress-strain sensor that exhibits an exponential increase in resistance with increasing tensile strain due to the polymer dethreading from the CD rings. The designed preparations of highly repeatable or highly responsive stress-strain sensors with good mechanical properties can help broaden their application in electrical devices.

Aggregation Behavior of Cyclodextrin-Based [3]Rotaxanes.

The aggregation of a cyclodextrin (CD)-based [3]rotaxane has been observed and analyzed in detail for the first time in this work. Although the hexagonal packing aggregation of CD-based polyrotaxane is a well known phenomenon, corresponding studies in terms of rotaxanes without any polymer structure have not been conducted so far, probably owing to the difficulty of the molecular design. We synthesized a series of [3]rotaxane species by using a urea-end-capping method and evaluated their aggregation behavior by XRD and SEM measurements. [3]Rotaxane species containing native CD rings showed clear signals assigned to the hexagonal packing by XRD measurement as did polyrotaxane; this proved their aggregation capability. Because the corresponding per-acetylated derivatives did not show this aggregation behavior, the driving force of this aggregation was suggested to be hydrogen bond formation among CD units. The effect of axle end structures and partial acetylation of CDs were also studied.

Thermoresponsive behavior of polyrotaxanes based on α-cyclodextrins threaded on poly(2-alkyl-2-oxazoline)-poly(ethylene glycol)-poly(2-alkyl-2-oxazoline) triblock copolymers

Polyrotaxanes with poly-2-alkyl-2-oxazoline blocking moieties have been successfully synthesized. The structure of the synthesized samples was confirmed by NMR spectroscopy, and the molar masses were measured by light scattering and GPC. The density of cyclodextrin rings on polyethylene glycol did not depend on the structure of poly-2-alkyl-2-oxazoline chains and ranged from 2 to 5. A high specific optical rotation of the prepared polyrotaxanes is found which is caused by the formation of hydrogen bonds between neighboring macrocycles. The behavior of water-salt solutions of synthesized polyrotaxanes depended on the size of the poly-2-alkyl-2-oxazoline side groups. Only polymers with poly-2-isopropyl-2-oxazoline and poly-2-n-propyl-2-oxazoline blocking moieties were thermoresponsive in aqueous solutions, and the phase separation temperature decreased at passage from a polymer with poly-2-isopropyl-2-oxazoline to a sample with poly-2-n-propyl-2-oxazoline. Aqueous solutions of polyrotaxanes with smaller side groups were molecularly dispersed at all temperatures, and the polymer with poly-2-butyl-2-oxazoline blocking chains did not dissolve in water.

Structural Distortion of β-Cyclodextrin Plays a Key Role in the pH-dependent Host-Guest Chemistry with Doxorubicin, Evident by the Electrochemical and Molecular Dynamics Approach.

β-Cyclodextrin (β-CD) is the potential drug carrier to deliver antitumor drugs like doxorubicin (DOX). However, the mechanism for the inclusion complex formation is still unclear and needs to be explored. This study investigated the effect of pH on the inclusion of DOX into thiolated β-CD (β-CD-SH) by electrochemical and molecular dynamics (MD) simulation. The electrochemical study shows a clear difference at different pH values. The redox peak due to the DOX is strongly influenced by pH. At neutral pH, the peak intensity decreases with time, while slight variation is observed at acidic and basic pH, depicting the association of DOX to the β-CD-SH cavity at neutral pH. Also, due to the association, the charge transfer resistance variation increased with time at neutral pH and decreased at basic and acidic pH. The electrochemical study was further supported by MD simulation, suggesting that the cyclodextrin (CD) ring gets slightly elongated due to the flipping of glucose units, specifically at neutral pH leading to a strong association. Also, another significant result observed that the DOX forms an inclusion complex with β-CD-SH in quinol conformation, not in quinone. Briefly, the study provides the necessary molecular binding information for designing an effective β-CD-based targeted drug delivery system.

Cover Feature: O‐Acylative Vinylation of Cyclodextrin‐Based [3]Rotaxane Towards Rotaxane Crosslinkers (Eur. J. Org. Chem. 12/2023)

The Cover Feature illustrates the acylation reaction of cyclodextrin (CD)-based [3]rotaxane. In this reaction system, one [3]rotaxane has 36 hydroxyl groups on two CD units, and excess of methacryl anhydride was added, as shown on the background. However, approximately only one methacryl unit (highlighted by yellow color) was introduced to one CD ring when the reaction condition was properly designed, probably owing to the steric hindrance. As a result, the product could be used as a [3]rotaxane crosslinker to afford network polymer crosslinked by through-space bonding. Cover design by Yosuke Akae. More information can be found in the Research Article by Y. Akae and T. Takata.

Stretchy electrodes that can keep up with an octopus

Materials for bioelectronics must often strike a compromise between mechanical and electrical properties. In a talk at the ACS Fall 2022 meeting last week, Stanford University chemical engineer Zhenan Bao described her approach to designing polymers that bridge that gap, combining high electrical conductivity with soft, stretchy, tissue-like mechanical properties. Conductive polymers are in some ways ideal for making bioelectronics. Unlike conventional electronic materials, such as silicon and metal, they can be inherently soft and stretchable. But improving their electronic properties typically comes at a cost: the more crystalline a polymer is, the higher its electrical conductivity—and the less it will stretch. Bao and her team decided to separate out these competing priorities by developing a polymer that interlocks parts that are each optimized for conductivity, mechanical properties, or photopatternability. The best polymer design started with a polyethylene glycol (PEG) backbone strung with sliding cyclodextrin rings, which were decorated with

Ion Selectivity and Permeation Mechanism in a Cyclodextrin-Based Channel.

Synthetic ion channels are a promising technology in the medical and materials sciences because of their ability to conduct ions. Channels based on cyclodextrin, a cyclic oligomer of glucose, are of particular interest because of their nontoxicity and biocompatibility. Using molecular dynamics-based free energy calculations, this study identifies cyclodextrin channel types that are best suited to serve as synthetic ion channels. Free energy profiles show that the connectivity in the channel determines whether the channel is cation-selective or anion-selective. Furthermore, the energy barrier for ion transport is governed by the number of glucose molecules making up the cyclodextrin units of the channel. A detailed mechanism is proposed for ion transport through these channels. Findings from this study will aid in designing cyclodextrin-based channels that could be either cation-selective or anion-selective, by modifying the linkages of the channel or the number of glucose molecules in the cyclodextrin rings.

One-Pot Synthesis of Asymmetrically Difunctionalized Oligomaltosides by Cyclodextrin Ring Opening.

The synthesis of pure difunctionalized hexa‐, hepta‐ and octamaltosides was performed by one‐pot chemical reaction from perbenzoylated cyclodextrin. Oligomaltosides with azide, propargyl or allyl on reducing end and an unprotected hydroxyl group on non‐reducing end were obtained from perbenzoylated α‐, β‐ and γ‐cyclodextrin with 12 to 48 % yields.

Dapsone- gel as a novel platform for acne treatment: In vitro evaluation and In vivo performance and histopathological studies in acne infected mice

The uniqueness of dapsone, 4,4′-diaminodiphenylsulfone (DPS) is attributed to its dual antimicrobial and anti-inflammatory effects. Nevertheless, DPS limited solubility in water makes its topical use in treatment of dermatological conditions limited. This study aimed to formulate and test the activity of DPS as a gel by its inclusion into a cyclodextrin ring. The interaction between DPS and methyl β-cyclodextrin (Kleptose® Crysemb) in the solution state was investigated using phase solubility technique. Aqueous solubility of DPS increased linearly as a function of the Kleptose® Crysemb concentration with a phase diagram classified as AL-type according to Higuchi and Connors. Moreover, interaction between the drug and the used cyclodextrin molecule was further investigated using differential scanning calorimetry and X-ray diffraction. The inclusion of the drug into core of the cyclodextrin molecule disrupted the crystalline nature of the drug forming crystalline form of higher solubility. The prepared complex was further incorporated in a thermo-sensitive Pluronic F127 gel, to ease the application on the skin. To assess the prepared gel anti-acne activity, in vivo testing in acne-induced inflammation mouse model was performed. DPS gel exhibited superior anti-inflammatory and healing activities compared to reference anti-acne antibiotic Aknemycin®. Additionally, the prepared DPS gel exhibited equipotent antimicrobial effect to that of reference antibiotic Aknemycin®. Our topical DPS formulation therefore provides an efficient strategy for treatment of dermatological indications, such as acne and for alternative treatment of leprosy.

Modification of Supramolecular Membranes with 3D Hydrophilic Slide-Rings for the Improvement of Antifouling Properties and Effective Separation.

A three-dimensional (3D) strategy for the fabrication of ethylene vinyl alcohol (EVAL) membranes with a dynamic surface was developed based on sliding supramolecular polymer brushes (SSPBs). The SSPBs with a 3D hydrophilic structure were introduced into the alkyne-EVAL membrane matrix via an azide-alkyne click coupling reaction. The self-mobile hydrophilic slide-rings in the SSPB provided a proactive exclusion system. This resulted in reduced direct contact of the membrane surface with multiple pollutants such as bovine serum albumin (BSA) and oil droplets. The EVAL-SSPB membrane demonstrated increased surface hydrophilicity, underwater oleophobicity, and antifouling properties. More importantly, the abundant hydrophilic rings in the membrane matrix result in supramolecular assembly and efficient hydrophilic sliding channels. This resulted in a dramatic increase in the water flux [2000 L/(m2 h)] while retaining a 96% rejection of BSA and oil/water emulsions. The results of the study indicate that three effects of the cyclodextrins rings, i.e., the hydrophilic effect, the exclusion effect, and the sliding effect, enabled the improved membrane performance. The demonstrated 3D fabrication strategy is versatile, facile, and scalable, which allows for its application to various other membranes. The fabricated materials possess excellent permeability and separation efficiencies, which make them attractive candidates for use as separation membranes with novel functions.

Direct and Regioselective Di‐α‐fucosylation on the Secondary Rim of β‐Cyclodextrin

AbstractInvited for the cover of this issue is the group of Marthe Walvoort at the University of Groningen. The image depicts a cyclodextrin ring as a dartboard, which is hit with fucose darts at specific positions to give a di‐fucosylated product. Read the full text of the article at 10.1002/chem.201806090.

Characterization of a novel extracellular α-amylase from Ruminococcus bromii ATCC 27255 with neopullulanase-like activity.

Ruminococcus is one of the keystone bacteria of the human colonic microbiota and is highly specific for utilization of resistant starch via formation of amylosomes. Here, we present the characteristics of an extracellular amylase, Rbamy5, in Ruminococcus bromii. In an in silico study, it showed low homology with any other known amylases, but it was evolutionarily classified as a GH13_36 subfamily intermediary amylase. Recombinant Rbamy5 exhibited maximum activity toward amylose (384 ± 26 U·mg-1) over soluble starch (254 ± 3 U·mg-1), amylopectin (46.1 ± 2.6 U·mg-1) and pullulan (72.5 ± 0.41 U·mg-1) at 45 °C and pH 5.0. It was also able to degrade small substrates such as maltotriose (G3), maltotetraose (G4), and maltopentaose (G5) into maltose (G2). Despite lacking a specific N-terminal domain, Rbamy5 opened the cyclodextrin ring, which resembles those of neopullulanase. Moreover, it accumulated short α-(1 → 6)-branched maltooligosaccharides from soluble starch and maltosyl-β-cyclodextrin (G2-β-CD), while panose was solely derived from pullulan. These results suggest that Rbamy5 may have a role to provide branched maltooligosaccharides to stimulate the growth of beneficial microorganisms in the human intestine.

Comparison of the cytotoxic, genotoxic and apoptotic effects of Sugammadex and Neostigmine on human embryonic renal cell (HEK-293)

Acetylcholinesterase inhibitors, including Neostigmine, have been used to reverse neuromuscular blockage for many years. Sugammadex reverses this blockage using its gamma cyclodextrin ring, a mechanism that differs from that of cholinesterases and so circumvents the side effects of Neostigmine. Although the superiority of Sugammadex to Neostigmine has been outlined in several clinical studies, to our knowledge, there is not any research into cell culture that compares the cytotoxic, genotoxic and apoptotic effects of the two drugs. Hence, this is the first study to compare the cytotoxic, genotoxic and apoptotic effects of different dosages of both drugs on human embryonic renal (HEK-293) cells. In this study, the cytotoxicity, genotoxicity and apoptotic effects of Sugammadex and Neostigmine on HEK-293 cells were analyzed with using the MTT, Comet Assay and Flow Cytometric Annexin-V methods, respectively. The results demonstrate that Neostigmine at 50, 100, 250, and 500 µg/mL is more cytotoxic than equivalent dosages of Sugammadex. Neostigmine at 500 and 1000 µg/mL was found to be more genotoxic, and Neostigmine at 500 µg/mL had a statistically higher risk of causing apoptosis and necrosis than Sugammadex (p<0.05). Neostigmine administered in-vitro in the same doses as Sugammadex had greater cytotoxic, genotoxic and apoptotic effects on HEK-293 cells.

Hydration properties and water structure in aqueous solutions of native and modified cyclodextrins by UV Raman and Brillouin scattering

AbstractWe have studied aqueous solutions of native and chemically modified cyclodextrins (CDs) by means of UV Raman and Brillouin scattering. Analysis of the spectral profile of the OH‐stretching Raman signal, which is sensitive to the intermolecular organization of water, reveals a remarkable reduction of the population of ordered tetrahedral water structures inside the hydration shell of substituted CDs. As a remarkable result, this destructuring effect seems to be mainly related to the number of substituted hydroxyl groups in the CD ring rather than to the chemical nature of the substituent group. UV Brillouin scattering experiments confirm the structural picture emerging from the UV Raman study, also providing an estimate of the activation energy associated to the collective H‐bond restructuring mechanism in CD solutions. Overall, the results provide a coherent description of the water–solute interactions in aqueous solutions of CDs.

Correction: Characterization of hydroxypropyl-beta-cyclodextrins used in the treatment of Niemann-Pick Disease type C1.

[This corrects the article DOI: 10.1371/journal.pone.0175478.].

Characterization and Comparison of the Solid State Inclusion Compounds of alfa-, beta-Cyclodextrins and its 2-Hydroxypropyl Derivatives with Uracil and 5-fluorouracil

The objective of the present work was to obtain and evaluate the solid inclusion complexes of a-, b-cyclodextrins and hydroxypropyl-a-, hydroxypropyl-b-cyclodextrins derivatives with uracil (U) and anti-cancer agent 5-fluorouracil (5FU). The thermogravimetry (TG), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy in attenuated total reflectance mode (FTIR-ATR) and scanning electron microscopy (SEM) were used to characterize these inclusion compounds. New information on the physicochemical behavior of these solid state complexes synthesized by melting in solution was obtained. Corelating the experimental data we found that the complexation occurs for each host:guest system thus, the preparation method exhibited a real efficiency to interaction achievements. The inclusion capability and the thermal stability of the studied complexes were due to both the flexibility and the size of the cyclodextrin ring as well the stereoelectronic effect of the U or 5FU molecule. We appreciated that the complexes between U or 5FU with 2-hydroxypropyl derivatives of a- and b- CD have the largest content of guest and are the most stable. The obtained results could be useful in formulation of the pharmaceutical products and also in drug delivery.

Polyrotaxanes could boost battery performance

Replacing the anode in commercial lithium-ion batteries with a silicon-based version could improve how much charge a battery can hold. But silicon anodes have been difficult to develop because they massively expand and contract as a battery charges and discharges, causing particles in the anode to break apart and the battery to fail. Now, a team led by Ali Coskun and Jang Wook Choi at Korea Advanced Institute of Science & Technology has developed highly elastic polymers that, when added to a silicon anode, can relieve the stress of charging and discharging while holding the silicon particles together (Science 2017, DOI: 10.1126/science.aal4373). The researchers devised a unique polymeric network made of the conventional linear polymer polyacrylic acid covalently linked to polyrotaxanes containing mechanical bonds. In the polyrotaxanes, an amine functionalized polyethylene glycol chain is threaded through a number of cyclodextrin rings. During battery charging, as the silicon anode expands, the

Theranostic Prodrug Vesicles for Imaging Guided Codelivery of Camptothecin and siRNA in Synergetic Cancer Therapy.

The construction of prodrugs has been a popular strategy to overcome the limitations of chemotherapeutic drugs. However, complicated synthesis procedures and laborious purification steps make the fabrication of amphiphilic prodrugs rather difficult. By harnessing the concept of host-guest interaction, we designed and prepared a supra-amphiphile consisting of a dendritic cyclodextrin host and an adamantane/naphthalimide-modified camptothecin guest through glutathione-responsive disulfide linkage. This host-guest complex could self-assemble in aqueous solution to give nanosized vesicles. When the disulfide bond in adamantane/naphthalimide-modified camptothecin was cleaved by glutathione, the fluorescence of the freed adamantane/naphthalimide unit showed a significant red shift with enhanced intensity. Such glutathione-responsive fluorescence change allows for intracellular imaging and simultaneous monitoring of drug release in real time. On account of abundant positively charged amine groups on the supramolecular vesicle surface, siRNA (siPlK1) could be efficiently loaded on the vesicle. The gel retardation and fluorescence experiments proved that the siPlK1 was successfully bonded to the supramolecular vesicle. The vesicle with dendritic cyclodextrin ring exhibited negligible cytotoxicity even at high concentrations, avoiding the shortcoming of cytotoxicity from commonly used gene vectors. In vitro studies demonstrated that the loaded siRNA was transported into cancer cells to improve cancer therapeutic efficacy. Thus, we developed a prodrug-based supramolecular amphiphile via the host-guest interaction with better therapeutic performance than free camptothecin. The assembled system was utilized as a drug/gene vector to achieve combinational gene therapy and chemotherapy with a synergistic effect, providing an alternative strategy to deliver both prodrug and therapeutic gene.

One-pot synthesis of block-copolyrotaxanes through controlled rotaxa-polymerization

The aqueous reversible addition fragmentation chain-transfer (RAFT) copolymerization of isoprene and bulky comonomers, an acrylate and an acrylamide in the presence of methylated β-cyclodextrin was employed for the first time to synthesize block-copolyrotaxanes. RAFT polymerizations started from a symmetrical bifunctional trithiocarbonate and gave rise to triblock-copolymers where the outer polyacrylate/polyacrylamide blocks act as stoppers for the cyclodextrin rings threaded onto the inner polyisoprene block. Statistical copolyrotaxanes were synthesized by RAFT polymerization as well. RAFT polymerization conditions allow control of the composition as well as the sequence of the constituents of the polymer backbone which further effects the CD content and the aqueous solubility of the polyrotaxane.