Inclusion complexes of pantoprazole with β-cyclodextrin and cucurbit[7]uril: experimental and molecular modeling study

The inclusion complexes of the proton pump inhibitor (PPI) pantoprazole sodium (PNZ_Na) with β-cyclodextrin (βCD) and cucurbit[7]uril (CB[7]) have been investigated. Fluorescence spectroscopy and electrospray ionization mass spectrometry (ESI-MS) were used to characterize these complexes. The fluorescence intensity of PNZ_Na was remarkably enhanced by both hosts, indicating the formation of the complexes. Nevertheless, the two hosts are of comparable cavity size their effect on the fluorescence of PNZ_Na was quite different. The ESI-MS data on the other hand confirmed the formation of a 1:1 PNZ_Na: host inclusion complexes for the two hosts. We further utilized molecular dynamics to shed more light on the mechanism of complexation and on the stability of these complexes in aqueous media. The complexes were stabilized over the 20 ns of simulation time mainly via hydrogen bonding interactions in addition to hydrophobic effects and van der Waals interactions. Snapshots collected during the simulations for both complexes have clearly shown that the mode of insertion of PNZ into the two host’s cavities are different which explain the difference in fluorescence enhancement of PNZ obtained in presence of each of these hosts.     

Encapsulation of a β-carboline in cucurbit[7]uril

Inclusion of a biological photosensitizer and prototype of β-carbolines, norharmane (NHM), into the cavity of cucurbit[7]uril (CB[7]) has been investigated for the first time, by using ¹H NMR and UV–visible spectroscopy, and ab initio calculations. Protonated NHM forms a very stable host–guest complex with CB[7] in aqueous solution, with a binding constant of (9.0 ± 0.5) × 10⁴ M^?1. The encapsulation of NHM into CB[7] has driven the prototropic equilibrium of NHM to protonated NHM (NHMH⁺) at neutral pH. A pH titration for the host–guest complex revealed a moderate shift of the acid–base equilibrium in the ground-state (from 7.2 to 7.9), which may be caused by the low polarity microenvironment of the CB[7] cavity. The CB[7] provides a binding pocket for the hydrophobic molecule, and the polar, carbonyl-lined portals offering an anchoring site for the positive charge of the cationic species NHMH⁺.     

A heterowheel [3]pseudorotaxane by integrating β-cyclodextrin and cucurbit[8]uril inclusion complexes

A heterowheel [3]pseudorotaxane was prepared by integrating two binary inclusion complexes of β-cyclodextrin-hydroxynaphthalene (β-CD·3) with a cucurbit[8]uril-viologen derivative (CB[8]·2), in which simultaneous molecular recognition of the adamantine moiety in 2 by β-CD and the charge-transfer interaction of 3 with the viologen nucleus of 2 in the cavity of CB[8] are two crucial factors for the formation of the quaternary complex.     

Supramolecular assemblies of cucurbit[n]urils and 4-aminopyridine controlled by cucurbit[n]uril size (n = 5, 6, 7 and 8)

The binding interactions between 4-aminopyridine (4-AP) and a series of cucurbit[n]urils (Q[5], Q[6], TMeQ[6], Q[7], Q[8]) have been studied using ¹H NMR spectroscopy, UV–vis absorption spectroscopy, isothermal titration calorimetry (ITC) and X-ray crystallography. The data indicates that the Q[5]@4-AP complex exhibits exo binding, which is not observed in the other four host-guest complexes. Furthermore, X-ray crystallography clearly reveals how the Q[n]s bind with 4-AP to form complexes, for example Q[5] forms an outer-surface complex, whilst Q[6], TMeQ[6] and Q[7] formed 1:1 host and guest type complexes, and Q[8] formed a stable 1:2 ternary complex due to its large cavity, which can accommodate two 4-AP molecules.     

A Comparative Study of Complexation of β-Cyclodextrin,Calix[4]arenesulfonate and Cucurbit[7]uril with Dye Guests: Fluorescence Behavior and Binding Ability

The complexation behaviors of acridine red (AR), neutral red (NR) and rhodamine B (RhB) dye guest molecules by three kinds of supramolecular hosts, including β-cyclodextrin (β-CD), calix[4]arene tetrasulfonate (C4AS) and cucurbit[7]uril (CB[7]), have been investigated by means of fluorescence spectra in aqueous citrate buffer solution (pH 6.0). The results obtained show that the three hosts, possessing different types of cavity, lead to various complexation-induced fluorescence of dye guests, and present different binding ability and molecular selectivity. The complexation stability constants decrease in the order of NR > AR > RhB for C4AS and CB[7] hosts, while in the order of RhB > AR > NR for β-CD host. Particularly, CB[7] displays the strongest binding ability with NR (K _S = 33300 M^? 1), and provides the molecular selectivity of 4.8 for NR/AR pairs. Although the binding ability of C4AS for present dye guests is weaker than CB[7], but the molecular selectivity of the two hosts are nearly equivalent. β-CD shows stronger binding ability with RhB (K _S = 5880 M^? 1) as comparison with CB[7] and C4AS. Furthermore, the solvent effects and salt effects during the course of complexation have also been investigated.     

Coordination and recognition of lanthanide cations by a methyl-substituted cucurbit[6]uril derived from 3α-methyl-glycoluril

The interactions between a series of lanthanide cations (Ln³⁺) and a methyl-substituted cucurbit[6]uril derived from 3α-methyl-glycoluril (SHMeQ[6]) in the presence of [CdCl₄]^2 ? as a structure-directing agent in aqueous HCl solutions (6.0 mol·L ^? 1) have been investigated. The formation of ionic radius-dependent complexes, the crystal structures of six of which have been obtained, shows the recognition ability of SHMeQ[6] towards lanthanide cations. For example, SHMeQ[6] forms molecular capsule-like complexes with the two lightest lanthanide cations, La³⁺ and Ce³⁺; molecular pairs with Nd³⁺, Sm³⁺, Eu³⁺ and Gd³⁺, and no solid crystals are formed with the heavier lanthanides.     

Preparation and characterization of a novel single crystal of Th(Ⅳ) with cucurbit[6]uril

One single crystal based on Th~(4+) and cucurbit[6]uril(CB6) in nitric acid aqueous solutions was synthesized by slow evaporation method. The single crystal was characterized by elemental analysis,single crystal X-ray diffraction, XRD, FT-IR and TGA. The complexed cation of Th~(4+) is a ten coordinated structure, in which the central thorium ion is coordinated by six monodentate water molecules and two bidentate nitrates. While CB6, as a second-sphere ligand, coordinates with the water molecules of [Th(NO_3)_2(H_2 O)_6]~(2+) through the formation of hydrogen bonding. Two other nitrate ions act as the counter anions. Besides, there are two free water molecules in the crystal system. The formation of the Th~(4+)-CB6 complex can contribute to the study of the coordination of CB6 and the extraction of Th~(4+) in HNO_3 system     

Effects of sequence context on the binding of tryptophan-containing peptides by the cucurbit[8]uril–methyl viologen complex

This paper describes a novel assay for measuring the relative extent of peptide binding in a large parallel format and the use of this assay to explore the effects of sequence context on the binding of tryptophan (Trp)-containing peptides by the synthetic receptor comprising the noncovalent complex between cucurbit[8]uril and methyl viologen (i.e. Q8√MV). The extent of quenching of Trp fluorescence upon binding to Q8√MV was used to measure the relative extent of binding and thus the relative affinities of 104 Trp-containing peptides, in parallel, using a fluorescence plate reader. This study resulted in the remarkable observation that the identity of the amino acid residues at positions adjacent to the Trp-binding site has little if any influence on the binding affinity. This finding suggests that Q8√MV should be effective for the recognition of Trp residues within a broad range of peptide sequences.     

Host–guest complexes of the antituberculosis drugs pyrazinamide and isoniazid with cucurbit[7]uril

The potential use of cucurbit[7]uril (CB[7]) as an excipient in oral formulations for improved drug physical stability or for improved drug delivery was examined with the antituberculosis drugs pyrazinamide (pyrazine-2-carboxamide) and isoniazid (isonicotinohydrazide). Both drugs form 1:1 host–guest complexes with CB[7] as determined by ¹H nuclear magnetic resonance spectrometry, electrospray ionisation mass spectrometry and molecular modelling. Drug binding is stabilised by hydrophobic effects between the pyridine and pyrazine rings of isoniazid and pyrazinamide, respectively, to the inside cavity of the CB[7] macrocycle as well as hydrogen bonds between the hydrazide and amide groups of each drug to the CB[7] carbonyl portals. At pH 1.5, isoniazid binds CB[7] with a binding constant of 5.6 × 10⁵ M^?1, whilst pyrazinamide binds CB[7] at pH 7 with a much smaller binding constant (4.8 × 10³ M^?1). Finally, CB[7] prevents drug melting through encapsulation. Where previously pyrazinamide displays a typical melting point of 189 °C and isoniazid 171 °C, by differential scanning calorimetry, no melting or degradation at temperatures up to 280 °C is observed for either drug once bound by CB[7].     

Complexation of [2.2]paracyclophane with β- and γ-cyclodextrins studied by HPLC and NMR

The NMR spectra of [2.2]paracyclophane with β- or γ-cyclodextrin in DMF-d₇ at room temperature do not show significant complexation, while HPLC of the complexes in mixed H₂O:alcohol solvents demonstrate complexation with different stoichiometries. At 243 K in DMF solution the H3 and H5 NMR signals of γ-cyclodextrin (but not β) exhibit complexation-induced chemical shifts denoting complex formation. According to HPLC, at room temperature the [2.2]paracyclophane complex with β-cyclodextrin in 20% H₂O:EtOH exhibits 1:2 stoichiometry with K ₁ = 1×10² ± 2, K ₂ = 9.0×10⁴ ± 2×10³ (K = 9×10⁶) while that with γ-cyclodextrin in 50% H₂O:MeOH exhibits 1:1 stoichiometry with K ₁ = 4×10³ ± 150 M⁻¹. Thermodynamic parameters for both complexes have been estimated from the retention time temperature dependence. For the β-cyclodextrin complexation at 25°C ΔG ⁰ _CD is −39.7 kJ mol⁻¹ while ΔH ⁰ _CD and ΔS ⁰ _CD are −88.2 kJ mol⁻¹ and −0.16 kJ mol⁻¹ K⁻¹. For γ-cyclodextrin, the corresponding values are ΔG ⁰ _CD = −20.5 kJ mol⁻¹, ΔH ⁰ _CD = −33.5 kJ mol⁻¹ and ΔS ⁰ _CD = −0.04 kJ mol⁻¹ K⁻¹.      

Host–guest interactions of a twisted cucurbit[15]uril with paraquat derivatives and bispyridinium salts

Host–guest complexations of a twisted cucurbit[15]uril with some paraquat derivatives and bispyridinium salts in aqueous solution are investigated by nuclear magnetic resonance, UV–vis spectrometry and isothermal titration calorimetry. These complexations are mainly enthalpy-driven.     

Primary photoprocesses of 3,3’-diethylthiacarbocyanine in the presence of cucurbit[7]uril: Laser flash photolysis and quantum chemical calculations

The effect of cucurbit[7]uril on the phototransformation of 3,3′-diethylthiacarbocyanine iodide dye in aqueous solution has been investigated by nanosecond laser flash photolysis. The presence of cucurbit[7]uril results in the formation of its complex with the dye molecule producing a dimer. The dimer formation is evident from the ground and triplet-triplet absorption spectra. The dimers in the triplet state are capable of electron transfer. The structure of the complexes is suggested on the basis of quantum chemical calculations.     

Encapsulation of 2,2′-(decane-1,10-diyl)-diisoquinoline into cucurbit[6]uril and α,α′,δ,δ′-tetramethyl-cucurbit[6]uril: formation of pseudorotaxanes and polypseudorotaxanes†

Host–guest complexation of cucurbit[6]uril and α,α′,δ,δ′-tetramethyl-cucurbit[6]uril with 2,2′-(decane-1,10-diyl)-diisoquinolinium has been investigated by ¹H NMR, UV and fluorescence spectroscopy in aqueous solution and by X-ray crystallography in solid state. Experimental data suggest that in the aqueous solution, both host molecules form [2]pseudorotaxanes with the host located over the decyl chain of the guest. In the solid state, neighbouring [2]pseudorotaxanes are linked by π?π and C–H?π interactions, eventually generating polypseudorotaxanes.     

Converging free energies of binding in cucurbit[7]uril and octa-acid host–guest systems from SAMPL4 using expanded ensemble simulations

Molecular containers such as cucurbit[7]uril (CB7) and the octa-acid (OA) host are ideal simplified model test systems for optimizing and analyzing methods for computing free energies of binding intended for use with biologically relevant protein–ligand complexes. To this end, we have performed initially blind free energy calculations to determine the free energies of binding for ligands of both the CB7 and OA hosts. A subset of the selected guest molecules were those included in the SAMPL4 prediction challenge. Using expanded ensemble simulations in the dimension of coupling host–guest intermolecular interactions, we are able to show that our estimates in most cases can be demonstrated to fully converge and that the errors in our estimates are due almost entirely to the assigned force field parameters and the choice of environmental conditions used to model experiment. We confirm the convergence through the use of alternative simulation methodologies and thermodynamic pathways, analyzing sampled conformations, and directly observing changes of the free energy with respect to simulation time. Our results demonstrate the benefits of enhanced sampling of multiple local free energy minima made possible by the use of expanded ensemble molecular dynamics and may indicate the presence of significant problems with current transferable force fields for organic molecules when used for calculating binding affinities, especially in non-protein chemistries.     

Molecular docking study on β-cyclodextrin Interactions of metobromuron and [3-(p-bromophenyl)-1-methoxy-1-methylurea]

The inclusion process involving β-cyclodextrin (β-cyclodextrin-CD) and phenylurea herbicide metobromuron (MB) has been investigated by using the MM+, PM3, B3LYP, HF, ONIOM2 and NBO methods. The binding and complexation energies for both orientations considered in this research are reported. The geometry of the most stable complex shows that the aromatic ring is deeply self-included inside the hydrophobic cavity of β-CD also an intermolecular hydrogen bond is established between host and guest molecules. This suggests that hydrophobic effect and hydrogen bond play an important role in the complexation process. The statistical thermodynamic calculations by PM3 demonstrate that 1:1?MB/β-CD complex is favored by a negative enthalpy change. Moreover, NBO calculations proved also that are a very useful means to quantify the interaction energies of the hydrogen bonds.     

The synthesis and molecular recognition study of β-cyclodextrin derivatives modified by spiro[2H-benzopyran-2,2′-indoline]

Introduction

Encapsulation of rifampicin by β-cyclodextrin and its methyl and hydroxy-propyl derivatives was studied in solid and solution phase.

Materials and Methods

The inclusion phenomenon was evidenced by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) analysis and fourier-transform infrared (FT-IR) spectroscopy and supplemented by proton nuclear magnetic resonance (¹H-NMR) spectroscopy. The host–guest stoichiometry (1:1) and stability constant were determined by solution calorimetry.

Results

The inclusion of drug was found to be exothermic process accompanied by small negative value of Gibbs free energy (ΔG°) and small positive value of entropy (ΔS°).

Conclusion

The magnitude of equilibrium constant (K) indicates that methyl-β-cyclodextrin has the best complex formation ability. Solubility, dissolution and partition coefficient studies also support the most effective behavior of methyl-β-cyclodextrin.     

Synthesis and Crystal Structure of a Binuclear Gadolinium(III) Complex Bridged by Cucurbit[6]uril

Cucurbit[6]uril (Q6, Figure 1) is a macrocyclic ligand with interesting complexing properties. In contrast to other macrocyclic ligands, such as crown ethers, cryptands or calixarenes, this ligand has a rigid structure offering a hollow core of about 5.5 …     

Inclusion complexes based α,ω-imidazolium based oligosiloxane (Im-PDMS) and cucurbit[7]uril (CB[7]) in aqueous solution

Inclusion complexes of α,ω-bisimidazolium oligosiloxane (Im-PDMS) and cucurbit[7]uril (CB[7]) in aqueous solution were studied. The binding interactions were monitored by ¹H NMR. Their annular aggregate morphologies were confirmed by TEM. The aggregation behavior of free Im-PDMS and Im-PDMS in 10^?4 CB[7] were investigated using surface tension measurement.