Stable Host Guest Research Articles

Determination of Binding Constants for the Complexes Between Heavy Metal Ions and Cucurbit[n]uril

AbstractOne of the major concerns worldwide is the rapid increase in water pollution with hazardous heavy metals. The Cucurbit[n]uril (CB[n]) structure provides an inner hydrophobic cavity accessible through two electrostatically negative portals with polar carbonyl groups, allowing for charged ion–dipole interaction between cationic species with excellent binding affinities. In this work we selected CB[5], and CB[7] for the titrimetric and electrochemical evaluation of the heavy metal complexes formed with Copper(II), Cadmium(II) and Lead(II). The host–guest interaction was found by either attenuation of the redox peaks, the formation of a new peak, or the slight shift in the redox peaks of the heavy metal ions. Titration data were obtained for CB[n] with the heavy metal solutions to determine the molar coefficient of binding. The stoichiometry of the complexes was 1 : 1 by Job′s plot. We calculated the binding constants using the Benesi–Hildebrand method achieving relatively good binding constants (K) ranging from (1.80±0.14)×105–(4.98±0.13)×105 M−1. The results showed that the complexes of Cadmium(II) and Lead(II) with both CB[5] and CB[7] are highly stable in aqueous media. Copper(II) was able to bind to the smaller sized portal of CB[5], whereas with CB[7] the heavy metal ion could not form a favourable complex. This phenomenon suggests that the CB[5] is an ideal host at forming stable host–guest interactions than their larger homologue.

Dihydroacridine-functionalized pillar[5]arene with optical response towards alanine derivative

Aiming at the construction of novel macrocycle-based fluorescence probes, herein we have designed and synthesized a new functionalized pillar[5]arene (P[5]A-Ac) with the pillar[5]arene as the macrocyclic host and the dihydroacridine moiety as the fluorescence indicator. The stable host–guest complexing between P[5]A-Ac and alanine derivative (Ala-OEt) was confirmed by Job’s plot, Uv–vis and 1H NMR titration experiments. More importantly, remarkable fluorescence color change from blue towards light yellow was observed upon adding Ala-OEt to the solution of P[5]A-Ac, implying the dihydroacridine-functionalized pillar[5]arene could serve as a new fluorescence probe for the detection of alanine derivative.

A comparative study of green solid contact ion selective electrodes for the potentiometric determination of Letrozole in dosage form and human plasma

Analysis of drugs clinically and their identification in biological samples are of utmost importance in the process of therapeutic drug monitoring, also in pharmacokinetic investigations and tracking of illicit medications. These investigations are carried out using a variety of analytical methods, including potentiometric electrodes. Potentiometric electrodes are a wonderful solution for researchers because they outperform other methods in terms of sustainability, greenness, and cost effectiveness. In the current study, ion-selective potentiometric sensors were assembled for the aim of quantification of the anticancer drug Letrozole (LTZ). The first step was fabrication of a conventional sensor based on the formation of stable host–guest inclusion complex between the cationic drug and 4-tert-butylcalix-8-arene (TBCAX-8). Two additional sensors were prepared through membrane modification with graphene nanocomposite (GNC) and polyaniline (PANI) nanoparticles. Linear responses of 1.00 × 10–5–1.00 × 10–2, 1.00 × 10–6–1.00 × 10–2 and 1.00 × 10–8–1.00 × 10–3 with sub-Nernstian slopes of 19.90, 20.10 and 20.30 mV/decade were obtained for TBCAX-8, GNC, and PANI sensors; respectively. The developed sensors were successful in determining the drug LTZ in bulk powder and dosage form. PANI modified sensor was used to determine LTZ in human plasma with recoveries ranging from 88.00 to 96.30%. IUPAC recommendations were followed during the evaluation of the electrical performance of the developed sensors. Experimental conditions as temperature and pH were studied and optimized. Analytical Eco-scale and Analytical GREEness metric were adopted as the method greenness assessment tools.

1,8-Dihydroxy Naphthalene-A New Building Block for the Self-Assembly with Boronic Acids and 4,4'-Bipyridine to Stable Host-Guest Complexes with Aromatic Hydrocarbons.

The new Lewis acid-base adducts of general formula X(nad)B←NC5H4-C5H4N→B(nad)X [nad = 1,8-O2C10H6, X = C6H5 (2c), 3,4,5-F3-C6H2 (2d)] were synthesized in high yields via reactions of 1,8-dihydroxy naphthalene [nadH2] and 4,4'-bipyridine with the aryl boronic acids C6H5B(OH)2 and 3,4,5-F3-C6H2B(OH)2, respectively, and structurally characterized by multi-nuclear NMR spectroscopy and SCXRD. Self-assembled H-shaped Lewis acid-base adduct 2d proved to be effective in forming thermally stable host-guest complexes, 2d × solvent, with aromatic hydrocarbon solvents such as benzene, toluene, mesitylene, aniline, and m-, p-, and o-xylene. Crystallographic analysis of these solvent adducts revealed host-guest interactions to primarily occur via π···π contacts between the 4,4'-bipyridyl linker and the aromatic solvents, resulting in the formation of 1:1 and 1:2 host-guest complexes. Thermogravimetric analysis of the isolated complexes 2d × solvent revealed their high thermal stability with peak temperatures associated with the loss of solvent ranging from 122 to 147 °C. 2d, when self-assembled in an equimolar mixture of m-, p-, and o-xylene (1:1:1), preferentially binds to o-xylene. Collectively, these results demonstrate the ability of 1,8-dihydroxy naphthalene to serve as an effective building block in the selective self-assembly to supramolecular aggregates through dative covalent N→B bonds.

Adamantane-Substituted Purine Nucleosides: Synthesis, Host–Guest Complexes with β-Cyclodextrin and Biological Activity

Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host-guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity.

Theoretical insight and molecular recognition of oxatub[4]arene-based organic macrocycle as a supramolecular host for antipsychotic drug risperidone

Neurological diseases such as schizophrenia and other psychotic disorders can be treated with one of the second-generation antipsychotic drugs, the aromatic benzisoxazole derivative, namely risperidone (RSP), which is hydrophobic; making it difficult to dissolve effectively into body fluids. Oxatub[4]arene (TA4) is a novel organic macrocycle with a π-electron-rich hydrophobic nanocavity and has previously been reported to form stable host–guest inclusion complexes with several aromatic compounds. This study carried out the theoretical investigation and molecular recognition of four RSP-docked hydroxylated TA4 (HTA4) conformers or RSP@HTA4. All structures were optimized and calculated using B3LYP/def2-SVP level theory with DFT-D4 dispersion correction. Complex conformer RSP@HTA4-III is proven to have the highest stability, least reactivity, and the formation is the most energetically favorable. By reviewing the ΔG value of the inclusion process, it was found that only the complex formation with HTA4-II and HTA4-III hosts was spontaneous. All non-covalent interactions involved and responsible for complex stabilization were described using NBO and NCI-RDG analysis. Further analysis using QTAIM characterized strong interactions within the complexes. In contrast, weak interactions were modeled using IGMH, followed by π-stacking interactions, which were specifically analyzed using LOLIPOP and IRI-π. The results of this pre-experimental study demonstrate and prove the excellent stability of RSP@HTA4. It also provides insight and support in developing an affordable and appropriate drug delivery system for RSP or similar drugs.

Host-guest complexation between cucurbit[7]uril and doxepin induced supramolecular assembly.

The supramolecular complexation of doxepin (DOX) with cucurbit[7]uril (CB7) was investigated in aqueous solution. The results indicated the formation of a host-guest complex, as verified by complexation-induced chemical shifts in the NMR experiments and supported by quantum-chemical calculations, in which the alkylammonium tail of DOX was found to be encapsulated inside the CB7 cavity, while the tricyclic moiety remained exposed to bulk water. Isothermal titration calorimetry and dye-displacement experiments provided a moderate binding affinity (104 M-1). Interestingly, the partial encapsulation of DOX by the CB7 macrocycle led to the development of a supramolecular assembly at a low millimolar concentration, as verified by NMR and dynamic light scattering (DLS) measurements, which showed homogeneous size distributions with an average diameter of 1700 nm.

Molecular Dynamic Simulation Analysis on the Inclusion Complexation of Plumbagin with β-Cyclodextrin Derivatives in Aqueous Solution.

Stable encapsulation of medically active compounds can lead to longer storage life and facilitate the slow-release mechanism. In this work, the dynamic and molecular interactions between plumbagin molecule with β-cyclodextrin (BCD) and its two derivatives, which are dimethyl-β-cyclodextrin (MBCD), and 2-O-monohydroxypropyl-β-cyclodextrin (HPBCD) were investigated. Molecular dynamics simulations (MD) with GLYCAM-06 and AMBER force fields were used to simulate the inclusion complex systems under storage temperature (4 °C) in an aqueous solution. The simulation results suggested that HPBCD is the best encapsulation agent to produce stable host–guest binding with plumbagin. Moreover, the observation of the plumbagin dynamic inside the binding cavity revealed that it tends to orient the methyl group toward the wider rim of HPBCD. Therefore, HPBCD is a decent candidate for the preservation of plumbagin with a promising longer storage life and presents the opportunity to facilitate the slow-release mechanism.

Cucurbit[7]uril as a matrix solid-phase dispersion for the extraction of quaternary ammonium pesticides from vegetables and their determination using HPLC–UV

Cucurbit[7]uril (Q[7]) was first used as a dispersant sorbent material in a matrix solid-phase dispersion for the simultaneous extraction of four quaternary ammonium pesticides from vegetables before analysis using high-performance liquid chromatography with UV detection. Q[7] exhibited a better selectivity and adsorption capability for these compounds, which is due to its ability to bind selectively organic molecules into its hydrophobic cavity and to form stable host–guest inclusion complexes. Various parameters affecting the extraction were investigated and optimized, such as sorbent/sample mass ratio, grinding time, rinsing and eluting conditions. Under optimized conditions, the proposed method exhibited a linear response in the concentration range of 1–100 μg·kg−1, satisfactory recoveries for eight types of vegetable samples (>70%), and high repeatability (RSD < 9.0%). The limits of quantification were between 0.43 μg·kg−1 and 0.99 μg·kg−1, which is nearly 50 times lower than the maximum residue limits established by the European Council.

Molecular Entrapment of Polymers by Pyrogallol[4]arenes.

Macromolecular recognition systems are difficult to construct because extremely high recognition ability is required to form a stable host-guest complex toward macromolecules. Herein, we report a novel host-guest recognition motif based on C-propylpyrogallol[4]arene (PgC3) and a commercially available polymer, polyethylene glycol (PEG). The results show that PgC3 can selectively entrap PEG with higher molecular weights to form bilayered host-guest complex structures. Interestingly, this host-guest recognition is strong enough that PgC3 is able to adsorb PEG from an aqueous solution efficiently.

Hydroxy-Propil-β-Cyclodextrin Inclusion Complexes of two Biphenylnicotinamide Derivatives: Formulation and Anti-Proliferative Activity Evaluation in Pancreatic Cancer Cell Models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy.

Host-guest complexation studies of NO3, NO2, CO2, and N2 gas with the calix[4]arene molecule.

Calix[n]arenes (abbreviated as CX[n]) are the macro-molecules based on phenol groups with a hydrophobic cavity to encapsulate a gas or small molecules. They are used as molecular vehicles. For instance, these molecules are used in the activation of the solubility of monomers in the specific media and in pharmaceutical drug delivery. The limit of the development of gaseous pollutants will be a vital subject in the future. The polluting gases NO3, NO2, CO2, N2, etc., need cage molecules, such as CX[4], to be encapsulated. In this report, the red shift of the H-bonding interactions of the CX[4]-gas (by adding the gas inside or outside the cavity) is clearly explained by the vibrational analysis. The electronic spectra of the complexes of CX[4] with NO3, NO2, CO2, and N2) exhibit a blue-shift pick in comparison with the ones observed for the CX[4] molecule. The electrophilic and nucleophilic sites of the stable host-guest have been investigated. Additionally, the non-covalent interactions have been calculated based on the reduced density gradient RDG and QTAIM theory.

Inclusion Complexes of Melphalan with Gemini-Conjugated β-Cyclodextrin: Physicochemical Properties and Chemotherapeutic Efficacy in In-Vitro Tumor Models.

β-cyclodextrin (βCD) has been widely explored as an excipient for pharmaceuticals and nutraceuticals as it forms stable host–guest inclusion complexes and enhances the solubility of poorly soluble active agents. To enhance intracellular drug delivery, βCD was chemically conjugated to an 18-carbon chain cationic gemini surfactant which undergoes self-assembly to form nanoscale complexes. The novel gemini surfactant-modified βCD carrier host (hereafter referred to as 18:1βCDg) was designed to combine the solubilization and encapsulation capacity of the βCD macrocycle and the cell-penetrating ability of the gemini surfactant conjugate. Melphalan (Mel), a chemotherapeutic agent for melanoma, was selected as a model for a poorly soluble drug. Characterization of the 18:1βCDg-Mel host–guest complex was carried out using 1D/2D 1H NMR spectroscopy and dynamic light scattering (DLS). The 1D/2D NMR spectral results indicated the formation of stable and well-defined 18:1βCDg-Mel inclusion complexes at the 2:1 host–guest mole ratio; whereas, host–drug interaction was attenuated at greater 18:1βCDg mole ratio due to hydrophobic aggregation that accounts for the reduced Mel solubility. The in vitro evaluations were performed using monolayer, 3D spheroid, and Mel-resistant melanoma cell lines. The 18:1βCDg-Mel complex showed significant enhancement in the chemotherapeutic efficacy of Mel with 2–3-fold decrease in Mel half maximal inhibitory concentration (IC50) values. The findings demonstrate the potential applicability of the 18:1βCDg delivery system as a safe and efficient carrier for a poorly soluble chemotherapeutic in melanoma therapy.

Cyclodextrins Can Entrap Zearalenone-14-Glucoside: Interaction of the Masked Mycotoxin with Cyclodextrins and Cyclodextrin Bead Polymer.

Zearalenone (ZEN) is a Fusarium-derived xenoestrogenic mycotoxin. In plants, zearalenone-14-O-β-d-glucoside (Z14G) is the major conjugated metabolite of ZEN, and is a masked mycotoxin. Masked mycotoxins are plant-modified derivatives, which are not routinely screened in food and feed samples. Cyclodextrins (CDs) are cyclic oligosaccharides built up from D-glucopyranose units. CDs can form stable host–guest type complexes with lipophilic molecules (e.g., with some mycotoxins). In this study, the interaction of Z14G with native and chemically modified β- and γ-CDs was examined employing fluorescence spectroscopy and molecular modeling. Furthermore, the removal of Z14G from aqueous solution by insoluble β-CD bead polymer (BBP) was also tested. Our results demonstrate that Z14G forms the most stable complexes with γ-CDs under acidic and neutral conditions (K ≈ 103 L/mol). Among the CDs tested, randomly methylated γ-CD induced the highest increase in the fluorescence of Z14G (7.1-fold) and formed the most stable complexes with the mycotoxin (K = 2 × 103 L/mol). Furthermore, BBP considerably reduced the Z14G content of aqueous solution. Based on these observations, CD technology seems a promising tool to improve the fluorescence analytical detection of Z14G and to discover new mycotoxin binders which can also remove masked mycotoxins (e.g., Z14G).

Hydrogen bond directed molecular recognition in water in a strapped-porphyrin-cyclodextrin assembly

A water soluble, phenanthroline-strapped zinc porphyrin bearing four arylsulfonate groups formed a stable host–guest complex with two per-[Formula: see text]-methylated [Formula: see text]-cyclodextrin cavities. In the host–guest assembly, the zinc porphyrin was capable of binding imidazole within the cavity between the zinc(II) ion and the phenanthroline strap in an aqueous medium. The formation of a hydrogen bond between the imidazole NH and the nitrogen atoms of the phenanthroline was an essential element of the binding event, as shown by comparative binding studies with a non-strapped tetrasulfonated zinc porphyrin and with [Formula: see text]-methylimidazole. This hydrogen bonding in an aqueous medium was possible due to the protected hydrophobic environment created by the cyclodextrins around the phenanthroline strap. This type of binding event may provide a biomimetic approach to study water soluble heme protein models.

Smart chiral magnetic nanoparticles for highly efficient enantioseparation of tryptophan enantiomers

Herein, we report a simple and facile strategy to prepare one kind of smart chiral magnetic nanoparticles (Fe3O4@PDA@PNG-CD) with high enantioselectivity via combining mussel-inspired polydopamine (PDA) chemistry with surface-initiated atom transfer radical polymerization for effective enantioseparation of tryptophan enantiomers (dl-Trp). The PDA thin layer plays a pivotal role in fabricating high-density poly(N-isopropylacrylamide-co-glycidyl methacrylate)-β-cyclodextrin (PNG-CD) smart polymer brushes onto the Fe3O4 NPs. The grafted PNG-CD plays a significant role in greatly boosting the enantioselectivity of the Fe3O4@PDA@PNG-CD, which is composed of the poly(N-isopropylacrylamide-co-glycidyl methacrylate) (PNG) copolymer chains with numerous appended β-cyclodextrin (β-CD) units. The β-CD units serve as chiral selectors capable of selectively recognizing and binding l-tryptophan (l-Trp) into their cavities by forming stable host–guest inclusion complexes of β-CD/l-Trp, and the PNIPAM chains act as microenvironmental adjustors for the inclusion constants of β-CD/l-Trp complexes. Operating temperature and initial concentrations of dl-Trp are two important factors that significantly affect the separation efficiency of dl-Trp and the enantioselectivity of the Fe3O4@PDA@PNG-CD. Furthermore, the Fe3O4@PDA@PNG-CD also demonstrates satisfactory recycling and excellent magnetic separability from enantiomeric solution. Such smart chiral magnetic NPs with high enantioselectivity developed in this study show great potentials in direct enantioseparation of various chiral compounds.

Anion Recognition by Organometallic Calixarenes: Analysis from Relativistic DFT Calculations

The physical nature of the noncovalent interactions involved in anion recognition was investigated in the context of metalated calix[4]arene hosts, employing Kohn–Sham molecular orbital (KS-MO) theory, in conjunction with a canonical energy decomposition analysis, at the dispersion-corrected DFT level of theory. Computed data evidence that the most stable host–guest bonding occurs in ruthenium complexed hosts, followed by technetium and molybdenum metalated macrocyclic receptors. Furthermore, the guest’s steric fit in the host scaffold is a selective and crucial criterion to the anion recognition. Our analyses reveal that coordinated charged metals provide a larger electrostatic stabilization to anion recognition, shifting the calixarenes cavity toward an electron deficient acidic character. This study contributes to the design and development of new organometallic macrocyclic hosts with increased anion recognition specificity.

Stable host–guest complexes of bis-2,6-pyridinedicarboxylate iron(III) with dihydroxybenzenes

The high reactivity of iron(III) complexes towards phenolic compounds, such as catechol, is well known. We show here that concealing the iron(III) site by ligands helps to obtain stable host–guest iron(III) complexes with phenolic compounds. Host–guest complexes of Htriam[Fe(2,6-pdc)2] with catechol and resorcinol (where 2,6-pdc=2,6-pyridinedicarboxylate and Htriam is mono-protonated 6-phenyl-1,3,5-triazine-2,4-diamine) were prepared and characterized. The observed color for the inclusion complex of Htriam[Fe(2,6-pdc)2] with catechol in the solid state has a distinction from the colored species generated in solution by interactions between the same components. The solid state structures of these two host–guest complexes have differences in the CO distances of dihydroxybenzene ligands as well as the arrangements of π-stacks; in the case of resorcinol, phenolic character is retained. In the catechol host–guest complex the CO distances in catechol are 1.310(7) and 1.370(6)Å, whereas in the resorcinol host–guest complex similar CO distances are 1.368(4) and 1.374(3)Å. The dissimilarity in the CO bond distances of catechol in the host–guest complex suggests charge-transfer through a semi-quinone cation radical type interactions with the iron ion showing an absorption at 570nm for the solid sample. A prior activation of catechol in the second coordination sphere through a ligand–catechol interaction is depicted.

Straightforward metal-free synthesis of an azacalix[6]arene forming a host–guest complex with fullerene C60

The straightforward metal-free synthesis of an azacalix[6]arene from simple aryl units is described together with its full characterization. This macrocycle features a rare 1,2,4,5-alternate conformation and is able to form a 1 : 1 stable host–guest complex with C60.

An ultra-sensitive sensor based on β-cyclodextrin modified magnetic graphene oxide for detection of tryptophan

A novel, ultra-sensitive and selective sensing platform was fabricated for detection of tryptophan (Trp) based on β-cyclodextrin modified magnetic graphene oxide (MGO-CD) nanocomposites. Magnetic Fe3O4 modified graphene oxide (MGO) was prepared by a simple coprecipitation method, then β-CD was conjugated on the surface of MGO through strong hydrogen bond and hydrophobic interaction. The sensitivity was obviously improved due to the synergistic effects between Fe3O4 and graphene oxide (GO), which would enhance the electron transfer rate as well as increase the surface area to capture a large amount of β-CD. Furthermore, the graft of β-CD had strong recognition capability for Trp to form stable host–guest inclusion complexes leading to the promotion of selectivity. The MGO-CD modified glassy carbon electrode (MGO-CD/GCE) was characterized by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV), and it revealed extraordinary electrochemical response towards the determination of Trp. Under the optimized conditions, the electrochemical sensor showed a wide linear range from 5.0×10−7M to 7.5×10−4M with a low detection limit of 3.1×10−7M (S/N=3). The proposed method displayed good reproducibility and excellent stability, which could be validated for commercial amino acid preparation sample, and satisfactory results were received. This strategy might provide the new clue for the clinic application.