Inclusion of parabens in β-cyclodextrin: A solution NMR and X-ray structural investigation

A parallel study was conducted of the inclusion of alkyl parabens (guests) in the host β-cyclodextrin (β-CD). ¹H NMR data indicated an insertion of the guest phenyl ring into the β-CD cavity. The stoichiometry of each complex was 1:1, as determined by a continuous variation method that utilises the chemical shifts of the host protons. These chemical shifts were additionally used to determine the association constant yielding K values of 1631, 938, 460 and 2022 M^? 1 at 298 K for the methyl-, ethyl-, propyl- and butyl paraben solution state complexes, respectively. NOE experiments conducted on the methyl paraben solution complex indicated that the phenolic group of the guest was located at the secondary rim of the cyclodextrin cavity. Solid state structure analyses of the methyl and propyl paraben β-CD complexes were performed. Both complexes crystallised at ambient temperature in the space group C2, Z = 4 with a host to guest ratio of 1:1. Additionally, a second crystal structure between methyl paraben and β-CD is reported. This complex crystallised at 7^oC in the space group P1, Z = 2 with a 1:1 host–guest stoichiometry.

¹H NMR and solid state structure analyses were conducted on the inclusion of alkyl parabens in the host β-cyclodextrin. Both indicated an insertion of the guest phenyl ring into the β-CD cavity.     

The complexation of flurbiprofen with β-cyclodextrin: a NMR study in aqueous solution

The complexation process between racemic flurbiprofen and β-cyclodextrin in solution was investigated by 1D and 2D proton NMR spectroscopy. In the presence of β-cyclodextrin, the aromatic protons of flurbiprofen were the most affected, suggesting a strong involvement of the phenyl groups in the inclusion mechanism. The stoichiometry of the complex was determined by the method of continuous variation, using the chemical induced shifts of both host and guest protons. The association constant, K_a of the obtained complex was calculated and found to be 2483.8 M^?1. On the other hand, signals belonging to the protons associated with the carboxyl group are split in the presence of β-cyclodextrin indicating enantiomeric differentiation. Rotating frame NOE spectroscopy, (ROESY), was used to ascertain the solution geometry of the host–guest complex. The result suggested that the flurbiprofen molecule fully penetrates the β-cyclodextrin cavity with the carboxyl group protruding from the primary hydroxyl side and the phenyl group close to the secondary rim.     

Investigation of the inclusion of the herbicide cycluron in native cyclodextrins by X-ray diffraction,nuclear magnetic resonance spectroscopy and isothermal titration calorimetry

The formation of inclusion complexes between the native cyclodextrins (CDs) and the urea herbicide cycluron has been investigated both in solution and in the solid state. Single-crystal X-ray structures of both the uncomplexed guest and the β-CD·cycluron complex were determined while powder X-ray diffraction was used to confirm complexation between γ-CD and cycluron in the solid state. Solution-state complexation between the herbicide and α-, β- and γ-CD was established using ¹H NMR spectroscopy and isothermal titration calorimetry (ITC). From the ¹H NMR spectroscopic studies 1:1 complex stoichiometry was indicated in all cases and association constant values (K) were determined as 228, 3254 and 155 for the complexes α-CD·cycluron, β-CD·cycluron and γ-CD·cycluron, respectively. Assigning a 1:1 host–guest ratio, the ITC technique produced K values of the same order as those determined using the spectroscopic method. The thermodynamic parameters ΔH, ΔS and ΔG obtained using ITC provide insights into the driving forces involved during complex formation.     

Inclusion complexes of Schiff bases as phytogrowth inhibitors

This article details the preparation, characterization and phytotoxic evaluation of several Schiff base inclusion complexes obtained from β-cyclodextrin and p-sulfonic acid calix[6]arene. The inclusion complexes (1:1 molar ratio) were prepared by mixing a 5 mmol L^?1 aqueous solution (containing 1 % DMSO) of Schiff bases (guests) with aqueous solution (containing 1 % DMSO) of 5 mmol L^?1 of β-cyclodextrin or p-sulfonic acid calix[6]arene (hosts). The host–guest systems were characterized via a series of NMR experiments. The ability of the complexes to interfere with the radicle elongation of Sorghum bicolor (dicotyledonous species) and Cucumis sativus (monocotyledonous species) was evaluated. After 48 h, the inclusion complexes inhibited the radicle elongation of both species from 11 to 56 %. The formation of inclusion complexes was also investigated theoretically by molecular dynamics simulations in aqueous solution through implicit approach. Based on the experimental observation, the phytotoxic activity evaluated can be attributed to the formation of host–guest systems. This was supported by the theoretical findings based on stable interaction energy analyses for all the studied supramolecular systems.     

1H NMR and calorimetric study on binding ability of cyclodextrins to isomeric pyridinecarboxylic acids in aqueous solution

Complex formation of α- and β-cyclodextrins with isomeric pyridinecarboxylic acids (picolinic, nicotinic and isonicotinic acids) in water were studied by calorimetry and ¹H NMR at 298.15 K. The obtained results revealed the weak 1:1 complex formation governed by the cavity dimensions and position of the carboxylic group in the pyridine ring. It was found that selective inclusion complex formation of α- and β-cyclodextrins with nicotinic and isonicotinic acids takes place. In the case of picolinic acid, the considerable role of external interactions and formation of less stable complexes were detected. The location of the carboxylic group in the meta-position of pyridine ring is more favorable for the effective binding. The pyridinecarboxylic acids are shallow inserted into α-cyclodextrin cavity possessing the smaller diameter, while they are deeply included into β-cyclodextrin cavity. Thermodynamic parameters of complex formation (K, Δ_cG⁰, Δ_cH⁰ and Δ_cS⁰) were calculated and discussed in terms of influence of reagents structure.     

Inclusion Interactions of Cucurbit[7]uril with Adenine and its Derivatives

Interactions of cucurbit[7]uril (Q[7] host) with guest adenine (g1), adenosine (g2) and 2′,3′-o-isopropylideneadenosine (g3) were studied in details by ¹H NMR, UV absorption spectroscopy, fluorescence spectroscopy and high performance liquid chromatography (HPLC) methods. We found that the suitable pH range for interaction was between 1 and 7, and the optimal pH range was between 2 and 4. The ¹H NMR analysis indicated that Q[7] selectively interacted with the adenine moiety of the guests g1 and g2, while Q[7] selectively interacted with the D-ribose sugar ring moiety of the guest g3. Moreover, ¹H NMR spectra showed that the exchange between the bound guest and the free guest was fast on the NMR time scale for the Q[7]-g1 and Q[7]-g2 systems. However, an obvious equilibrium between the bound host/guest and the unbound host/guest were observed in the Q[7]-g3 complex. Several methods were used to determine quantitatively the stability of the three host–guest inclusion complexes formed between Q[7] and the guests. The formation constants by UV and fluorescence were 1.90 × 10⁵ L mol^? 1 and 1.34 × 10⁵ L mol^? 1 for Q[7]-g1, 9.41 × 10⁴ L mol^? 1 and 4.24 × 10⁴ L mol^? 1 for Q[7]-g2, 4.50 × 10⁴ L mol^? 1 and 3.62 × 10⁴ L mol^? 1 for Q[7]-g3, respectively. HPLC method was also introduced to explore the interactions between Q[7] and the adenine and its derivatives. The formation constants of the host–guest inclusion complexes, as determined by HPLC, were 6.76 × 10⁴ L mol^? 1 for Q[7]-g1, 1.80 × 10⁴ L mol^? 1 for Q[7]-g2, 3.01 × 10⁴ L mol^? 1 for Q[7]-g3 respectively. Our study suggested that Q[7] could be a suitable host for the delivery of bioactive molecules, such as the adenine and its derivatives.     

Dissolution properties of cypermethrin/cyclodextrin complexes

Cypermethrin—a very effective pyrethroid-type insecticide—has been complexed with β-cyclodextrin and peracetylated-β-cyclodextrin with different guest content. Dissolution measurements by reversed phase HPLC method, together with UV-spectrophotometry, differential scanning calorimetry and thermogravimetry were applied to prove the inclusion complex formation and characterize the complexes. With the help of the thermal analysis the really complexed (strongly bound) and surface-bound guests were distinguished. All of the β-cyclodextrin complexes show better dissolution rate than the pure guest. In case of inclusion complexes an oversaturated solution was formed with extremely high concentration of active substance (6–19 mg L^?1) during the first couple of minutes then the concentration decreased gradually until it reached the equilibrium solubility value of the complex (2 mg L^?1). The cypermethrin/peracetylated-β-cyclodextrin complexes prepared with organic solvent method showed slightly retarded dissolution profile compared to the pure guest. The area under the dissolution curves was introduced for quantitative characterization of the dissolution rate. The release was found to depend on the complexed guest content of the samples. The continuous variation plots used first for this parameter gave information on the stoichiometry of the complexes: 1:2 cypermethrin/β-cyclodextrin and 1:1.25 cypermethrin/peracetylated-β-cyclodextrin.     

Interaction between tetramethylcucurbit[6]uril with α-furaldehyde-isonicotinyl-hydrazone hydrochloride

Interaction between tetramethylcucurbit[6]uril (TMeQ[6], host) and the hydrochloride salt of α-furaldehyde-isonicotinyl-hydrazone hydrochloride (FIHH⁺, guest) was investigated using X-ray crystallography and spectroscopic methods. X-ray crystallography showed that the π–π stacking effect and hydrogen bonding resulted in the formation of a dumbbell-shaped supramolecule which contained two FIHH⁺@TMeQ[6] host–guest inclusion complexes. The host–guest interaction provided identifiable changes in the vibrational frequencies in the IR spectra. ¹H NMR spectral analysis established a similar interaction model and revealed that TMeQ[6] preferred to include the furan moiety over the pyridine moiety of the FIHH⁺ guest molecule. Absorption spectrophotometric analysis suggested that the host and guest interact in a ratio of 1:1 with a stability constant K _s = (3.52 ± 0.74) × 10⁶ l mol^? 1.pH titration confirmed that the host–guest interaction led to a clear change in the protonation constant of the title guest. Quantum chemical calculations were used to determine the possible mechanism of formation of the dumbbell-shaped complex.     

An inclusion complex of β-cyclodextrin with mnt anion (mnt = maleonitriledithiolate) studied by induced circular dichroism

A new inclusion complex of β-cyclodextrin with sodium maleonitriledithiolate (Na₂mnt) was investigated by electronic spectra, induced circular dichroism (ICD), and quantum mechanics (QM) methods. The orientation of the guest anion inside the host cavity was studied by ICD spectra and analyzed by structural optimization using PM3 quantum chemical method. Finally, the inclusion constant was determined by both a linear and a non-linear fitting methods, which were based on the variation of ICD signals of the guest upon inclusion complexation with the host. The inclusion constant of Na₂mnt/β-cyclodextrin was estimated to be (2.45 ± 0.15) × 10³ or (3.10 ± 0.11) × 10³ M^?1 in solution by these two fitting methods.     

NMR Studies of Host–guest Complexes Between Monocarboxylic Acids and Amide-based Cyclophanes in Chloroform

Formation of host–guest complexes with acetic acid and benzoic acid was studied by NMR for amide-based octaazacyclophanes having pendant methyl ester arms; the cyclophanes were tetramethyl 2,9,18,25-tetraoxo-1,4,7,10,17,20,23,26-octaaza[10.10]paracyclophane-4,7,20,23-tetraacetate, its meta-isomer and analogues. Amide NH proton and CH₂ proton adjacent to amide C = O in every cyclophane host showed down-field NMR shifts in the presence of the guest acids in CHCl₃-d, suggesting the formation of 1:1 complexes in which the carboxyl group of an acid molecule formed two hydrogen bonds with the amide NH and C = O moieties of a host molecule. Since the complex formation competed with the dimerization of the guest acids, the monomer–dimer equilibrium was restudied by NMR and the equilibrium constant was determined to be 330 M^? 1 for acetic acid and 518 M^? 1 for benzoic acid. By using these values, the formation constants of the host–guest complexes were determined to be 8–51 M^? 1. The close contact between the host and guest molecules via hydrogen bonding was consistently confirmed by NMR shifts due to the ring current of aromatic group.     

Formation of an Inclusion Complex of a New Transition Metal Ligand in β-Cyclodextrin

The inclusion complex of a new transition metal ligand, 2,4,9-trithia-tricyclo[3.3.1.1^3,7]decane-7-carboxylic acid (2,4,9-trithia-adamantane-7-carboxylic acid, TPCOOH) in β-cyclodextrin was studied by ¹H NMR, 2D NOESY NMR spectroscopy, host-induced CD spectroscopy, and tandem mass spectrometry. ¹H NMR, MS–MS and NOESY data show that the TPCOOH guest forms a 1:1 inclusion complex with the host β-cyclodextrin. The NOESY experiments also show that TPCOOH is oriented in the complex with the thioketal end preferentially located at the larger opening of β-cyclodextrin. The orientation of the guest in the host molecule is also confirmed by the induced CD of the ligand, which shows a positive Cotton effect. An association constant of 660±20?M^?1 was determined by ¹H NMR titration for the complex at room temperature in D₂O.     

Host–guest interactions of 6-benzyladenine with normal and modified cucurbituril: 1H NMR,UV absorption spectroscopy and phase solubility methods

Guest–host inclusion complexes between 6-benzyladenine (6-BA), cucurbit[7]uril (Q[7]), symmetrical tetramethylcucurbit[6]uril (TMeQ[6]) and meta-hexamethyl-substituted cucurbit[6]uril (HMeQ[6]) in aqueous solution were investigated by ¹H NMR, UV absorption spectroscopy and phase solubility studies. The ¹H NMR spectra analysis revealed that the hosts selectively bound the phenyl moiety of the guests. Absorption spectroscopic analysis defined the stability of the host–guest inclusion complexes. A host:guest ratio of 1:1 was measured quantitatively as (5.63 ± 0.26) × 10⁴, (1.94 ± 0.17) × 10³ and (2.89 ± 0.23) × 10³ mol L^? 1 for the Q[7]-6-BA, TMeQ[6]-6-BA and HMeQ[6]-6-BA systems, respectively. Phase solubility diagrams were analysed through rigorous procedures to obtain estimates of the complex formation constants for Q[n]-6-BA complexation. The formation constants were (1.29 ± 0.24) × 10⁴ L mol^? 1 for Q[7]-6-BA, (3.20 ± 0.17) × 10³ L mol^? 1 for TMeQ[6]-6-BA and (3.52 ± 1.01) × 10³ L mol^? 1 for TMeQ[6]-6-BA. Furthermore, phase solubility studies showed that 6-BA solubility increased as a function of Q[7], TMeQ[6] and HMeQ[6] concentrations. The thermodynamic parameters of the complex formation were also determined. The formation of inclusion complexes between 6-BA and Q[7] was enthalpy controlled, suggesting that hydrophobic and van der Waals interactions were the main driving forces. Our results demonstrated that the complexation of 6-BA with Q[n] could be used to improve the solubility of 6-BA.     

Molecular encapsulation of Valganciclovir by β-cyclodextrin influences its binding to bovine serum albumin: a spectroscopic study

We report, in this paper, the stoichiometry, the binding constant and the structure of the β-cyclodextrin complex of the famous drug Valganciclovir. We investigate the influence of the complex formation of Valganciclovir with β-cyclodextrin, in the binding strength of the drug to the model carrier protein bovine serum albumin. Based on the electronic absorption, fluorescence and 2D rotating-frame Overhauser effect spectroscopy (ROESY) NMR spectral data, it follows that Valganciclovir forms a 1:1 complex with β-cyclodextrin. The β-CD molecule encapsulates the aliphatic chain of the substituted ester molecule. The association constant value of the drug-protein binding in the presence of β-cyclodextrin decreases from that in the absence of β-cyclodextrin, i.e., from that in the case of free drug, i.e. from 3.99 × 10⁴ M^?1 to 5.21 × 10³ M^?1. We compare the results of the binding of the drug to bovine serum albumin in free- and β-cyclodextrin-complex forms.     

Complexation studies of pioglitazone hydrochloride and β-cyclodextrin: NMR (1H, ROESY) spectroscopic study in solution

Pioglitazone hydrochloride (PIO) is an agonist of the peroxisome proliferator-activated receptor γ (PPARγ), used to treat diabetes. ¹H-NMR spectroscopic analysis of varying ratios of β-cyclodextrin (β-CyD) and PIO in D₂O confirmed the formation of β-CyD–PIO inclusion complex in aqueous solution. The 1:1 stoichiometry of β-CyD–PIO inclusion complex was determined by Scott’s plot method and binding constant (K _a ) was calculated to be 155 M^?1. 2D ROESY experiments confirmed that the phenyl ring of PIO act as a guest and deeply penetrate in β-CyD cavity from wider as well as narrower rim side and form two 1:1 stable inclusion complexes. Some of the PIO protons exhibited splitting, in the presence of β-CyD, indicating chiral differentiation of PIO by β-CyD.     

Thermodynamics of inclusion complex formation of hydroxypropylated α- and β-cyclodextrins with aminobenzoic acids in water

Calorimetry, densimetry, ¹H NMR and UV–vis spectroscopy were used to characterize inclusion complex formation of hydroxypropylated α- and β-cyclodextrins with meta- and para-aminobenzoic acids in aqueous solutions at 298.15 K. Formation of more stable inclusion complexes between para-aminobenzoic acid and cyclodextrins was observed. The binding of aminobenzoic acids with hydroxypropyl-α-cyclodextrin was found to be enthalpy-governed owing to the prevalence of van der Waals interactions and possible H-binding. Complex formation of hydroxypropyl-β-cyclodextrin with both acids is mainly entropy driven. The increased entropy contribution observed in this case is determined by dehydration of solutes occurring during the revealed deeper insertion of aminobenzoic acids into the cavity of hydroxypropyl-β-cyclodextrin. By comparing complex formation of aminobenzoic acids with native and substituted cyclodextrins it was found that the availability of hydroxypropyl groups slightly influenced the thermodynamic parameters and did not change the binding mode or driving forces of interaction.     

Competitive Binding of Tolmetin to β-Cyclodextrin and Human Serum Albumin: <Superscript>1</Superscript>H NMR and Fluorescence Spectroscopy Studies

The host–guest interaction of tolmetin (TOL) with β-cyclodextrin (β-CD) and the influence of human serum albumin (HSA) on the formation of the inclusion complex were studied by 1D and 2D NMR spectroscopy. The TOL/β-CD inclusion complex formed at a molar ratio of 1:1 with a binding constant value of 2164.5 L·mol^?1. Data analysis showed that the addition of 10 μmol·L^?1 of HSA weakened the strength of TOL binding to β-CD (K _a = 1493 L·mol^?1). The interaction of TOL with HSA in the absence and presence of β-CD was studied by analyzing the fluorescence quenching data. The Stern–Volmer quenching constants and the binding constants are found to be smaller in the presence of β-CD, suggesting that β-CD hinders the strong interaction of TOL with HSA by complex formation. Additionally, the presence of β-CD does not induce conformational and microenvironmental changes on HSA.     

Characterization of β-cyclodextrin inclusion complex with procaine hydrochloride by 1H NMR and ITC

The inclusion of local anesthetic drug procaine hydrochloride by β-cyclodextrin was investigated by 1D and 2D proton NMR spectroscopy and isothermal titration calorimetry (ITC) at 298 K. The stoichiometry of the complex was determinate by the method of continuous variation, using the chemical induced shift of both host and guest protons. The association constant K, of the obtained complex was calculated and found to be 293.17 M^?1. Rotating frame NOE spectroscopy, was used to ascertain the solution geometry of the host–guest complex. The result reveals that the procaine molecule penetrates into the β-cyclodextrin cavity with the aromatic ring. The energetics of complexation process is investigated by ITC technique. The analysis indicates that the complexation of procaine by β-CD is an exothermic process and show that both enthalpy and entropy contribute to the binding process. The obtained value for the association constant is in good agreement with that obtained from NMR.     

Diverse Modes of Guest Inclusion in a Cyclodextrin: X-ray Structural and Thermal Characterization of a 4:3 β-cyclodextrin—Cyclizine Complex

Abstract

1-Diphenylmethyl-4-methylpiperazine (cyclizine) is an antiemetic drug which forms an inclusion complex with β-cyclodextrin of formula (β-cyclodextrin)₄ · (cyclizine)₃ · 50H₂O. This species crystallizes in the monoclinic space group P2₁ with a = 15.246(1), b = 65.075(5), c = 15.609(1) Å, β = 102.62(1)° and Z = 2 formula units. Complex water content and the host:drug stoichiometric ratio were determined by thermogravimetry and UV spectrophotometry respectively. Differential scanning calorimetry showed that the crystals dehydrate in at least two stages and begin to decompose from approximately 250°C. The crystal structure was solved by a combination of Patterson search and direct methods. Isotropic refinement converged at R = 0.094 for 8806 reflections with I > 2σ(I). The unusual stoichiometry is accounted for as follows: the four β-cyclodextrin molecules comprising the asymmetric unit occur as two independent head-to-head dimers, each formed by O—H…O hydrogen bonding across the macro-cyclic secondary surfaces. One dimer contains two cyclizine guest molecules in head-to-tail orientation, thus accounting for two distinct modes of drug inclusion. In the second dimer, only one β-cyclodextrin molecule is significantly occupied by a cyclizine molecule (in a mode analogous to one of those in the first dimer), the other half of the dimer being largely devoid of guest. A possible mechanism for the formation of this unusual structure is proposed and the crystal packing arrangement is shown to be based on a novel disrupted tetrameric channel motif.     

Unravelling the interaction between α-cyclodextrin with the thaumatin protein and a peptide mimic

G-protein-coupled receptors (GPCRs) are responsible for signal transduction; through these transmembrane proteins, our senses are evoked: sight, smell and taste. Thaumatin is a natural sweet-tasting protein that is 100,000 times sweeter than sucrose but its use in food products has been hampered due to a liquorice aftertaste. Thaumatin has been shown to bind to a class C GPCR and the active binding site of the thaumatin protein is known. Here, we report on the binding of a well-known food grade host: α-cyclodextrin to thaumatin. We show through a combination of one- and two-dimensional NMR experiments that α-cyclodextrin binds to aromatic residues on thaumatin with K_a = 8.5 ± 2.4 M ^? 1. We also synthesise a heptapeptide KTGDRGF that mimics the active binding site of thaumatin and show that α-cyclodextrin binds to the C-terminal solvent accessible phenylalanine residue of this peptide with K_a = 8.8 ± 3.1 M ^? 1. This indicates that α-cyclodextrin may interact with the active binding site on thaumatin, suggesting that α-cyclodextrin could be used to modify the interaction of thaumatin with GPCRs and hence its sweet-taste profile.     

Crystal and molecular structure of β-cyclodextrin inclusion complex with succinic acid

The crystal complex of β-cyclodextrin with succinic acid, intermediate product of hydrolysis reaction of succinic anhydride in the presence of β-cyclodextrin, was isolated and studied by X-ray analysis (monoclinic, space group P2₁, a = 15.1977(7) Å, b = 10.1763(5) Å, c = 20.6943(6) Å, β = 109.239(4)°, V = 3021.8(2) Å³, Z = 2, R ₁ = 0.0359, wR ₂ = 0.0947). It was proved that β-cyclodextrin and succinic acid form an inclusion complex, which exists in crystal state as a heptahydrate. The molecule of succinic acid is fully included in the β-cyclodextrin cavity with its carboxyl groups accessible for water molecules. Water molecules located at borders of cavity rims and in interstices between molecules of β-cyclodextrin participate in formation of intermolecular hydrogen bonds. The overall structure does not contain disordered fragments. The crystal conformation of succinic acid corresponds to one of possible conformers of the molecule in vacuo and is almost not disturbed by intermolecular interactions in crystal. Based on the analysis of structural features of the crystal conformation of succinic acid and character of its location in the β-cyclodextrin cavity, it was suggested that hydrolysis of succinic anhydride via ring opening and formation of succinic acid is mediated by cyclodextrin microenvironment and it likely occurs near the narrow rim of the macrocycle cavity.