A comparative study of inclusion complexes of flunarizine with alpha (α-CD) and beta-cyclodextrin (β-CD)

A detailed NMR (¹H, COSY, and ROESY) spectroscopic study of complexation of Flunarazine (FL) with α- and β-CD was carried out. ¹H NMR titration studies confirmed the formation of FL/α-CD and FL/β-CD complexes as evidenced by chemical shift variations of the proton resonances of both the CDs and FL. The stoichiometry of the complexes was determined to be 1:2 (FL/α-CD) and 1:1 (FL/β-CD) and overall binding constants were also calculated. It was confirmed with the help of ROESY spectral data that only one of the F-substituted aromatic ring and phenyl ring penetrate the α-CD cavity while both F-substituted aromatic rings as well as phenyl ring penetrates the β-CD cavity during complexation. The binding modes of FL/CD cavity interactions derived from ROESY experimental data show that the resulting complex of FL with β-CD possesses better induced fit interaction as compared to α-CD, which is responsible for the enhanced molecular stability with β-CD in comparison to α-CD. The mode of penetration of guest into the CD cavity and structures of the complexes has been established.     

A spectroscopic and molecular modeling studies of the inclusion complexes of orciprenaline and terbutaline drugs with native and modified cyclodextrins

The inclusion complexation behavior of orciprenaline (ORC) and terbutaline (TER) with α-CD, β-CD, HP-α-CD and HP-β-CD are examined by absorption, fluorescence, life time and molecular modeling methods. ORC and TER forms 1:1 (CD/drug) inclusion complexes in lower CD concentrations and 1:2 (CD/drug) inclusion complexes with higher CD concentrations. The inclusion of both drugs with HP-CDs was stronger than that of native CDs. Both drugs exhibit dual emission (excimer) in the CD solution, whereas in water single emission is seen. The hydrogen bonding and van der Waals interaction between the drugs and the CD plays an important role in the inclusion complexes. Computational results show the side chain of the drugs encapsulated in the CD cavity. The molecular modeling results by PM3 were in good agreement with the experimental results.     

Inclusion complexation of 4,4′-dihydroxybenzophenone and 4-hydroxybenzophenone with α- and β-cyclodextrins

The inclusion complexation behaviours of 4,4′-dihydroxybenzophenone (DHBP) and 4-hydroxybenzophenone (HBP) with α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD) were investigated using UV–visible fluorescence, time-resolved fluorescence, molecular modelling, scanning electron microscopy (SEM), FTIR, differential scanning calorimeter, X-ray diffraction, ¹H NMR and molecular modelling techniques. In both molecules, biexponential decay was observed in water, whereas triexponential decay was observed in the CD medium. The DSC thermogram of the DHBP/α-CD and DHBP/β-CD inclusion complex nanomaterials shows the endothermic peak at 60.8, 101.9, 119.6 and 112.8°C. The upfield chemical shift observed for HBP protons reveal that the phenyl ring (without hydroxyl substitution) entered the CD cavity and the hydroxyl group of HBP is exposed outside the CD cavity. The SEM image of DHBP appears as needle-shaped crystals on the micrometre scale, whereas the irregular bar shape was observed for HBP. Transmission electron microscopy images show that both guest molecules formed nano vesicles with α-CD and formed nano rods with β-CD.     

Tuning the cavity of cyclodextrins: altered sugar adaptors in protein pores

Cyclodextrins (CDs) have been widely used in host-guest molecular recognition because of their chiral and hydrophobic cavities. For example, β-cyclodextrin (βCD) lodged as a molecular adaptor in protein pores such as α-hemolysin (αHL) is used for stochastic sensing. Here, we have tuned the cavity and overall size of βCD by replacing a single oxygen atom in its ring skeleton by a disulfide unit in two different configurations to both expand our ability to detect analytes and understand the interactions of βCD with protein pores. The three-dimensional structures of the two stereoisomeric CDs have been determined by the combined application of NMR spectroscopy and molecular simulation and show distorted conformations as compared to natural βCD. The interactions of these synthetic βCD analogues with mutant αHL protein pores and guest molecules were studied by single-channel electrical recording. The dissociation rate constants for both disulfide CDs from the mutant pores show ～1000-fold increase as compared to those of unaltered βCD, but are ～10-fold lower than the dissociation rate constants for βCD from wild-type αHL. Both of the skeleton-modified CDs show altered selectivity toward guest molecules. Our approach expands the breadth in sensitivity and diversity of sensing with protein pores and suggests structural parameters useful for CD design, particularly in the creation of asymmetric cavities.     

Capillary electrophoresis and molecular modeling of the chiral separation of aromatic amino acids using α/β-cyclodextrin and 18-crown-6

In this work, chiral separation of enantiomers of three amino acids was achieved using capillary electrophoresis technique with α-cyclodextrin (αCD) as a running buffer additive. Only tryptophan has exhibited baseline separation in the presence of αCD, while the enantiomers of the other two amino acids, phenylalanine and tyrosine, were only partially separated. The addition of 18-crown-6 (18C6) as a second additive imparted only slight improvement to the separation of all enantiomers. On the other hand, all three racemic amino acid mixtures demonstrated no indication of separation when the larger cavity cyclodextrin members, β- and γCD, are used as running buffer chiral additives. However, remarkable improvements in the separation of the enantiomers of phenylalanine and tyrosine were obtained when 18C6 is used together with βCD as a running buffer additive. Surprisingly, tryptophan enantiomers were not separated by the dual additive system of cyclodextrin and crown ether. Using electrospray ionization mass spectrometry (ESI-MS), all amino acids were found to form stable binary complexes with individual hosts as well as ternary compounds involving the crown ether and the cyclodextrin. Furthermore, we used molecular dynamics (MD) simulations to build a clear picture about the interaction between the guest and the hosts. Most of these complexes remained stable throughout the simulation times, and the molecular dynamics study allowed better understanding of these supramolecular assemblies.     

The cavity size effect on the fluorescence properties of 4′-dimethylaminoacetophenone complexed with cyclodextrins

Fluorescence properties of excited 4^′-dimethylaminoacetophenone (DMAAP) complexed with α-, β-, and γ-cyclodextrins (CDs) were studied by means of steady state and time-resolved laser spectroscopy. The 1:2 DMAAP–α-CD and 1:1 DMAAP–β-CD complexes exhibited dual fluorescence in neutral aqueous solutions while only the fluorescence from the locally excited state was observed in the case of DMAAP complexed with γ-CD. The CD cavity size effect on the excited state dynamics of DMAAP–CD complexes was further discussed. It revealed that polarity effect introduced by the hydrophobic cavity is more important in controlling of the photochemistry of DMAAP than the restriction of molecular motion inside the CD cavity.     

Investigation on Non-covalent Complexes of Cyclodextrins with Li+ in Gas Phase by Mass Spectrometry

To investigate the non-covalent interaction between cyclodextrins (CD) and lithium ion, a stoichiometry of α-CD, β-CD, heptakis(2,6-di-O-methyl)-β-CD (DM-β-CD), or heptakis(2,3,6-tri-O-methyl)-β-CD (TM-β-CD) was mixed with lithium salt, respectively, and then incubated at room temperature for 10 min to reach the equilibrium. In posi-tive mode, the electrospray ionization mass spectrometry (ESI-MS) results demonstrated that lithium ion can conjugate to α-, β-, DM-β- or TM-β-CD and form 1:1 stoichiometric non-covalent complexes. The binding of the complexes was further confirmed by collision-induced dissociation. The dissociation constants K_d1 of four complexes (Li+α-CD, Li+β-CD, Li+DM-β-CD, and Li+TM-β-CD) were determined by mass spectrometric titration. The results showed K_d1 were 18.7, 26.7, 33.6, 30.5 μmol/L for the complexes of Li+ with α-CD, β-CD, DM-β-CD, and TM-β-CD, respectively. K_d1 for the Li⁺ complexes of β-CD is smaller than that of DM-β-CD due to its steric effect of the partial substituted -CH₃. The Kd1 for the Li⁺ complexes of DM-β-CD is nearly in agreement with that of TM-β-CD, indicating Li⁺ is more likely to locate in the small rim of DM-β-CD's hydrophobic cavity. The DFT results showed through electrostatic interaction, one Li+ can strongly conjugate to four neighboring oxygen atoms. For the (α-CD+Li)⁺ complex, one Li⁺ may also situate the small rim of α-CD's hydrophobic cavity to form a non-specific host-guest complex.     

Theoretical investigation to characterize the inclusion complex of α-lipoic acid and β-cyclodextrin

We simulated the docking of α-lipoic acid (α-LA) in β-cyclodextrin (β-CD) using two models. We considered in this study complexes formed by 1:1 host–guest stoichiometry in vacuo and in aqueous phase, using PM6, DFT and ONIOM2 hybrid calculations. The results obtained with PM6 method clearly indicate that the complexes formed are energetically favored with or without solvent, model 2 (α-LA entering the cavity of β-CD from its wide side by COOH group) is found more favored than model 1 (α-LA entering into the cavity of β-CD from its wide side by cyclic group), the preference being greater in the case of ONIOM2 calculations. In addition, NBO analysis gives that mutual interactions between the donor and acceptor orbitals of α-lipoic acid and β-CD plays an important role to the stabilization of such a complex. Finally, ¹H nuclear magnetic resonance (NMR) chemical shifts of free and complexed α-LA were calculated by the Gauge-Including Atomic Orbital (GIAO) method and compared with available experimental data. The results of GIAO calculations were analyzed and discussed.     

Esterase-mediated synthesis of optically active GABA analogues containing a stereogenic all-carbon quaternary carbon atom

Esterase from Horse Liver (HLAP) was able to hydrolyze a series of linear and cyclic β,β-dialkyl-γ-nitroesters, in spite of the well-known reluctance of hydrolytic enzymes to recognize and transform hindered substrates, such as those possessing a stereogenic quaternary carbon atom next to the reaction site. The resulting optically active γ-nitroesters gave access to optically active β,β-disubstituted γ-aminoacids as well as α,α-disubstituted succinic acids, both being biologically relevant compounds.     

Macroscopic observations of molecular recognition: discrimination of the substituted position on the naphthyl group by polyacrylamide gel modified with β-cyclodextrin

Macroscopic molecular recognition observations were realized using polyacrylamide-based gels modified with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), 1-naphthylmethyl (1Np), and 2-naphthylmethyl (2Np) moieties, which are denoted as αCD(x)-gel, βCD(x)-gel, 1Np(y)-gel, and 2Np(y)-gel, where x and y indicate the mol % of CD and Np moieties, respectively. The αCD(5)-gel did not adhere to either the 1Np(5)-gel or 2Np(5)-gel, whereas the βCD(5)-gel interacted with both to form alternating or checkered assemblies. Although the difference in the association constants of β-CD for the model polymers was small, the βCD(x)-gel successfully discriminated between 1Np(y)-gel and 2Np(y)-gel at the appropriate x and y.     

Effect of the ring size and asymmetry of cyclodextrins on their inclusion ability: a theoretical study

Effect of the ring size and asymmetry upon methylation of cyclodextrins (CDs) on their inclusion ability has been demonstrated for the inclusion complexes of native α-, β-, γ-CDs, dimethylated β-CD (DIMEB) and trimethylated β-CD (TRIMEB) with piperazine (PIZ) by PM3 and ONIOM calculations. In all complexes, PIZ prefers residing mostly in the central CD cavity. The complex stability in the order TRIMEB–PIZ > DIMEB–PIZ > α-CD–PIZ > γ-CD–PIZ > β-CD–PIZ indicates that the CD-ring asymmetry promotes the macrocycle deformation and inclusion ability. Our calculation results suggest that the inclusion complexes of both native and methylated CDs with PIZ in the gas phase are energetically stable, in addition to the β-CD–PIZ inclusion complex that has been evidenced thus far by X-ray crystallographic and spectroscopic analyses. Further calculations in the presence of water and adjacent CD molecules show that the increased intermolecular hydrogen bond interactions enhance the stability of β-CD–PIZ complex.     

倍半萜三醇的两种异构体的量子化学研究

用量子化学半经验方法 (PM3) ,研究了倍半萜三醇的两种异构体 :Bullatantriol和 1β ,4β ,7α -三羟基桉烷的电子结构 ,得到了它们的平衡几何构型、谐振动频率、红外强度、净电荷分布、键能和总能量 .结果表明 :1β ,4β ,7α -三羟基桉烷的总能量均较低 ,其热力学稳定性较强     

A comparative study of complexation of enalapril with α-, β- and γ-cyclodextrins in aqueous medium: structure elucidation of inclusion complexes using NMR spectroscopic and molecular mechanics methods

Structural studies of complexes of enalapril maleate with α-, β- and γ-cyclodextrins were carried by NMR spectroscopy and computational methods. The formation of complexes of enalapril with all the three cyclodextrins was established by chemical shift changes observed in the cavity protons of cyclodextrins in the presence of enalapril maleate. The stoichiometry of the complexes was determined to be 1:1 by ¹H NMR titrations studies using Scott’s method. Intermolecular cross peaks observed in the 2D ROESY spectra of mixtures of enalapril maleate with three cyclodextrins helped in establishing the probable structures of these inclusion complexes which were supported by molecular mechanics (MM2) studies. Enalapril forms 1:1 inclusion complex with all the studied cyclodextrins through aromatic ring. The mode of approach of aromatic ring to the α-cyclodextrin cavity was found to be different from those of β- and γ-cyclodextrins, which were identical.     

Atom-atom potential analysis of the complexing characteristics of cyclodextrins (host) with benzene and p-dihalobenzenes (guest)

Abstract

Intermolecular interaction and modelling calculations on the complexes of α-, β- and γ-cyclodextrins (host) with benzene and p-dihalobenzenes (guest) were performed. The complex formation mechanism between the host and guest molecules was evaluated from three-dimensional potential maps generated by the atom-atom potential method, and the molecular packing of the complexed compounds was visualized by a space-fill representation. Stable inclusion complexes only form when both the host and guest molecules experience a significant decrease in the complexing potential. The host and guest molecules have a maximum molecular surface contact at the minimum potential, which depends on both the cavity size and the molecular volumes of the guest molecules. The calculated interaction energies can be correlated to the association constants of complex formation determined from experiment. The molecular dynamics of the guest molecules are also discussed.     

铀酰-Salophen受体对α, β-不饱和羰基化合物及手性客体的分子识别

基于密度泛函理论(DFT)的计算方法,研究了不对称铀酰-salophen受体对α, β-不饱和羰基化合物客体及手性小分子的分子识别。理论计算结果表明:配合物中受体的U原子与客体的O3原子配位,且受体与客体之间结合能随受体上芳环取代基的增大而增大; R₂, R₃-系列配合物中U―O3键的稳定性比R₁-系列的更强;配位后的α, β-不饱和羰基化合物中C＝C与C＝O之间的共轭效应减弱。而且,通过圆二色谱(CD)及结合能计算表明:芘基铀酰-salophen (受体3)对(R)-1-(2-萘基)乙胺的分子识别选择性优于(S)-1-(2-萘基)乙胺。因而,这些研究结果为不对称铀酰-salophens具有分子识别能力提供了新的信息。     

Inclusion complexes between cyclic siloxanes and cyclodextrins: synthesis and characterization

Molecular inclusion complexes between cyclodextrins and cyclic siloxanes were prepared and characterized via a combination of liquid and solid state NMR, FT-IR, TGA, powder X-ray diffraction, SEM–EDS and elemental analyses. The crystalline complexes adopted the channel-type conformation. Depending from the size of both the cyclic sugar cavity and the silicon guest, various yields (between 0 and 41%) and host–guest molar ratios (between 1:1 and 4:1) were obtained. α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD) were observed to form crystalline inclusion complexes only with D₃ (cyclic dimethyltrisiloxane) due to steric effects, whereas the larger γ-cyclodextrin (γ-CD) formed inclusion complexes both with D₃, D₄ (cyclic dimethyltetrasiloxane) and D₅ (cyclic dimethylpentasiloxane). This study is believed to be the first step towards the selective removal of cyclic siloxanes impurities from commercial PDMS preparations.     

Inclusion complex of α-cyclodextrin and the extended viologen dication: a model of an insulated molecular wire

An extended viologen dication 1, containing one viologen subunit, was used as a model for the inclusion complex formation between cyclodextrin (CD) molecules and molecular wires comprising several subunits. UV–Vis and fluorescence spectroscopic measurements confirmed the formation of two types of the inclusion complexes 1:1 and 2:1 between αCD and 1 in the aqueous solution containing 20% of ethanol. The complex formation constants were obtained from the fluorescence spectral changes: K _a  = 25 ± 3 mM^?1 for [αCD–1] complex and K _a  = 0.21 ± 0.07 mM^?2 for [(αCD)₂–1] complex, respectively. Cyclodextrins βCD and γCD do not form the inclusion complexes with 1 in these aqueous solutions. The time-dependent differential capacitance measurements confirmed the adsorption of 1 in the form of a complex at the electrode/electrolyte interface. These studies were conducted with the aim to find the most suitable CD cavity that would separate individual molecular wires from each other on the electrode/electrolyte interface.     

A general procedure for the synthesis of isoxazolidin-5-ones

Conjugate addition of N-substituted hydroxylamines to α,β-unsaturated esters followed by cyclisation of the adducts with lithium bis (trimethylsily)amide provides the first general means of synthesising isoxazolidin-5-ones, the N-benzyl derivatives of which may be hydrogenolised to β-aminoacids.     

Comparison and correlation of in vitro, in vivo and in silico evaluations of alpha, beta and gamma cyclodextrin complexes of curcumin

In the present study investigated the effect of curcumin (CUR) alpha (α), beta (β) and gamma (γ) cyclodextrin (CD) complexes on its solubility and bioavailability. CUR the active principle of turmeric is a natural antioxidant agent with potent anti-inflammatory activity along with chemotherapeutic and chemopreventive properties. Poor solubility and poor oral bioavailability are the main reasons which preclude CUR use in therapy. Extent of complexation was β-CD complex (82 %) > γ-CD (71 %) > α-CD (65 %). Pulverization method resulted in significant enhancement of CUR (0.002 mg/ml) solubility with CUR α-CD complex (0.364 mg/ml) > CUR β-CD complex (0.186 mg/ml) > CUR γ-CD complex (0.068 mg/ml). Gibbs-free energy and in silico molecular docking studies favour formation of α-CD complex > β-CD complex > γ-CD complex. With reference to CUR, relative bioavailability of CUR α-CD, CUR β-CD and CUR γ-CD complexes were 460, 365 and 99 % respectively. CUR–CD complexes exhibited increased bioavailability with an increase in t_½, tmax, Cmax, AUC, Ka, and MRT; and a decrease in Ke, clearance and Vd values. AUC increase was CUR α-CD complex > CUR β-CD complex > CUR γ-CD complex. Significant difference (p < 0.05) was observed between CUR α-CD complex and CUR γ-CD complex by one-way ANOVA and Dunnett’s post hoc test for multiple comparison analysis. Correlation observed between in vitro, in vivo and in silico methods indicates potential of in silico and in vitro methods in CD selection.     

Determination of the inclusion complex constant between oleuropein and cyclodextrins by complexation theory

Oleuropein (OLE) is a major phenolic compound of olive leaf (Olea europaea) and has many therapeutic properties associated with olive leaf extracts. This work concerns the determination of the inclusion complex constant between OLE and cyclodextrins (CDs), based on the competition of two guests for the CD cavity, one being a dye and the other OLE. The dye used was methylorange (MO) and pH 3 was selected, since MO molar absorptivity at 500 nm is at maximum in this condition. A solution of MO, OLE, and α-CD or β-CD, with citrate buffer was used for determining the absorbance values. From these data and by appropriate mathematical modeling, the equilibrium constant for the formation of OLE:CD complexes were obtained: for OLE:α-CD K = 1,352.4 L mol^?1 (R ² = 0.9975) and for OLE:β-CD K = 1,827.9 L mol^?1 (R ² = 0.9991). The results show that OLE has a greater affinity for β-CD than for α-CD and given the relatively high constants, OLE:CD complexes have potential for giving longer shelf lives for OLE medicinal and food additive preparations.