Bimodal Complexations of Steroids with Cyclodextrins by a Flexible Docking Algorithm

A flexible docking algorithm was developed for studying the inclusion complexes of cyclodextrins with steroids in aqueous solution by an optimization method and an empirical function. The function is used to estimate the binding free energy including intermolecular interaction energy, the conformational energy change, and the solvation energy. The bimodal complexations of twelve steroids in β- and γ-CD cavities were studied by the algorithm. For the two orientations of the guests in the cavity, the possible binding regions were investigated, and the lowest energies for the inclusion complexes in the binding regions were obtained. The stability constant for each orientation was estimated from the optimized energy components by a quantitative model. Therefore, the preferential orientations of the guests were found out from the results finally.This revised version was published online in July 2005 with a corrected issue number.     

Fluorescence properties of (R)- and (S)-[1,1′-binaphthalene]-2,2′-diols solutions and their complexes with cyclodextrins in aqueous medium

Steady-state and time-resolved fluorescence techniques were used to study (R)- and (S)-[1,1′-binaphthalene]-2,2′-diol (1,1′-binaphthol or BINOL) dilute solutions of different polarity solvents, as well as their inclusion complexes with α- and βcyclodextrins (CDs) in water. BINOLs in dilute water solutions exhibited a surprisingly high fluorescence anisotropy that was explained as being due to the formation of fairly large order π–π stacking aggregates in aqueous polar media. Stoichiometries, formation constants and the changes of enthalpy and entropy upon inclusion were also obtained by measuring the variation of the fluorescence intensity with [CD] and temperature. Results agree with the formation of 1:1 stoichiometry complexes, but the association constants are rather low and very similar for both enantiomers. Molecular mechanic calculations in the presence of water were employed to study the formation of BINOL complexes with both α- and βCDs. For the most stable structures of any of the complexes only a small portion of the guests, in agreement with thermodynamics parameters and quenching experiments, penetrates inside the CD cavities. Driving forces for 1:1 inclusion processes may be dominated by non-bonded van der Waals host:guest interactions. The low guest:host binding constants and poor enantioselectivity of α- and βCDs for BINOLS may be a consequence of the BINOL aggregation in water.     

Complexation of ferrocene derivatives by the cucurbit[7]uril host: a comparative study of the cucurbituril and cyclodextrin host families

The formation of inclusion complexes between cucurbit[7]uril (CB[7]) and ferrocene and its derivatives has been investigated. The X-ray crystal structure of the 1:1 inclusion complex between ferrocene and CB[7] revealed that the guest molecule resides in the host cavity with two different orientations. Inclusion of a set of five water-soluble ferrocene derivatives in CB[7] was investigated by 1H NMR spectroscopy and calorimetric and voltammetric techniques. Our data indicate that all neutral and cationic guests form highly stable inclusion complexes with CB[7], with binding constants in the 10(9)-10(10) M(-)(1) and 10(12)-10(13) M(-1) ranges, respectively. However, the anionic ferrocenecarboxylate, the only negatively charged guest among those surveyed, was not bound by CB[7] at all. These results are in sharp contrast to the known binding behavior of the same guests to beta-cyclodextrin (beta-CD), since all the guests form stable inclusion complexes with beta-CD, with binding constants in the range 10(3)-10(4) M(-1). The electrostatic surface potentials of CB[6], CB[7], and CB[8] and their size-equivalent CDs were calculated and compared. The CD portals and cavities exhibit low surface potential values, whereas the regions around the carbonyl oxygens in CBs are significantly negative, which explains the strong affinity of CBs for positively charged guests and also provides a rationalization for the rejection of anionic guests. Taken together, our data suggest that cucurbiturils may form very stable complexes. However, the host-guest interactions are very sensitive to some structural features, such as a negatively charged carboxylate group attached to the ferrocene residue, which may completely disrupt the stability of the complexes.     

β-环糊精与有机胺之间包合作用的理论与实验研究

通过实验和理论计算方法研究了β-环糊精(CD)与乙二胺1及它的三个类似物: 二乙烯三胺2、三乙胺3和乙二胺四乙酸4之间的包合作用. 利用旋光法确定了β-CD与客体分子形成1:1型主–客体包合物, 在298.2 K下测定了包合物在水中的稳定常数(K). 采用半经验PM3方法考察了β-CD与短链脂肪胺1~7、环状脂肪胺8~11以及芳香胺12~13的分子间结合能力, 报道了β-CD与这些客体分子间的包合络合过程并讨论了这些包合体系之间的包合差异性. 变形能和水合能对包合体系的相互作用能的贡献均相当小. β-CD包合物的稳定性取决于主、客体分子之间的尺寸匹配. 对于β-CD与客体1~4形成的包合物而言, 旋光法测定的包合物的K值的顺序与PM3计算得到的包合物络合能绝对值的排序有很好的一致性.     

Recognition of ionic guests by ionic beta-cyclodextrin derivatives

Inclusion compounds of cationic, anionic, and neutral p-substituted derivatives of tert-butylbenzene complexed in beta-cyclodextrin and its ionic 6-mono and 6-hepta derivatives were systematically investigated by isothermal titration calorimetry (ITC). All inclusion compounds showed 1:1 stoichiometry with binding constants ranging from 10 to 3 x 10(6) M(-1). The binding free energies could be subdivided into apolar and electrostatic contributions. The electrostatic interactions could be quantitatively described by Coulomb's law by taking into account the degree of protonation of hosts and guests, the orientations of the guests within the hosts, and ion shielding as described by the Debye-Hückel-Onsager theory. The orientations of the guests within the cyclodextrin cavities were determined by ROESY NMR spectroscopy.     

pH-dependent binding of guests in the cavity of a polyhedral coordination cage: reversible uptake and release of drug molecules

A range of organic molecules with acidic or basic groups exhibit strong pH-dependent binding inside the cavity of a polyhedral coordination cage. Guest binding in aqueous solution is dominated by a hydrophobic contribution which is compensated by stronger solvation when the guests become cationic (by protonation) or anionic (by deprotonation). The Parkinson''s drug 1-amino-adamantane (‘amantadine’) binds with an association constant of 10⁴ M^–1 in the neutral form (pH greater than 11), but the stability of the complex is reduced by three orders of magnitude when the guest is protonated at lower pH. Monitoring the uptake of the guests into the cage cavity was facilitated by the large upfield shift for the ¹H NMR signals of bound guests due to the paramagnetism of the host. Although the association constants are generally lower, guests of biological significance such as aspirin and nicotine show similar behaviour, with a substantial difference between neutral (strongly binding) and charged (weakly binding) forms, irrespective of the sign of the charged species. pH-dependent binding was observed for a range of guests with different functional groups (primary and tertiary amines, pyridine, imidazole and carboxylic acids), so that the pH-swing can be tuned anywhere in the range of 3.5–11. The structure of the adamantane-1-carboxylic acid complex was determined by X-ray crystallography: the oxygen atoms of the guest form CH···O hydrogen bonds with one of two equivalent pockets on the internal surface of the host. Reversible uptake and release of guests as a function of pH offers interesting possibilities in any application where controlled release of a molecule following an external stimulus is required.     

Self-assembly of a water-soluble endohedrally functionalized coordination cage including polar guests

Coordination cages containing endohedrally functionalized aromatic cavities are scarce in the literature. Herein, we report the self-assembly of a tetra-cationic super aryl-extended calix[4]pyrrole tetra-pyridyl ligand into a water-soluble Pd(ii)-cage featuring two endohedral polar binding sites. They are defined by the four pyrrole NHs of the calix[4]pyrrole unit and the four inwardly directed α-protons of the coordinated pyridyl groups. The efficient assembly of the Pd(ii)-cage requires the inclusion of mono- and ditopic pyridyl N-oxide and aliphatic formamide guests. The monotopic guests only partially fill the cage''s cavity and require the co-inclusion of a water molecule that is likely hydrogen-bonded to the endohedral α-pyridyl protons. The ditopic guests are able to completely fill the cage''s cavity and complement both binding sites. We observed high conformational selectivity in the inclusion of the isomers of α,ω-bis-formamides. We briefly investigate the uptake and release mechanism/kinetics of selected polar guests by the Pd(ii)-cage using pair-wise competition experiments.

A tetra-cationic calix[4]pyrrole tetra-pyridyl ligand self-assembles into a water-soluble Pd(ii)-cage featuring two endohedral polar binding sites. The Pd(ii)-cage encapsulates pyridyl N-oxide and aliphatic formamide guests in water.     

Interactions of Nabumetone with γ-Cyclodextrin Studied by Fluorescence Measurements

The inclusion of the anti-inflammatory drug, Nabumetone (NAB), in γ-cyclodextrin (γ-CD) was studied by fluorescence measurements. The emission fluorescence spectrum, of NAB reveals a maximum whose intensity increases with the different γ-CD’s growing concentrations. The stoichiometery (1:1) and binding constants of the complexes at 15, 25, 35, and 45 °C were extracted from the analysis of the emission spectra of NAB. The thermodynamic parameters ΔH ° and ΔS ° for the formation of the complex were calculated from the temperature dependence of the binding constants and compared with previous results for similar complexes of NAB with α- and β-CDs. The location of NAB in the complex was determined using the fluorescence quenching method. Our results indicate that NAB is completely penetrated into the cavity of γ-CD.     

Interactions of Nabumetone with γ-Cyclodextrin Studied by Fluorescence Measurements

The inclusion of the anti-inflammatory drug, Nabumetone (NAB), in γ-cyclodextrin (γ-CD) was studied by fluorescence measurements. The emission fluorescence spectrum, of NAB reveals a maximum whose intensity increases with the different γ-CD’s growing concentrations. The stoichiometery (1:1) and binding constants of the complexes at 15, 25, 35, and 45 °C were extracted from the analysis of the emission spectra of NAB. The thermodynamic parameters ΔH ° and ΔS ° for the formation of the complex were calculated from the temperature dependence of the binding constants and compared with previous results for similar complexes of NAB with α- and β-CDs. The location of NAB in the complex was determined using the fluorescence quenching method. Our results indicate that NAB is completely penetrated into the cavity of γ-CD.This revised version was published online in July 2005 with a corrected issue number.     

Theoretical studies on the binding affinities of β-cyclodextrin to small molecules and monosaccharides

Equilibrium geometries and electronic structures of complexes between β-cyclodextrin (β-CD) and some small molecules as well as monosaccharides were investigated by Austin Model 1 (AM1) to obtain binding energy of the complexes. It was indicated that β-CD could bind the structurally similar solvent molecules and monosaccharides because of the negative binding energy of the complexes, and especially could show the chiral binding ability to monosaccharides with more hydroxyl groups, due to its chiral characteristics. The complexes were stabilized by the hydrogen bonding between β-CD and guests. Based on the AM1 optimized geometries, the IR spectra were calculated by AM1 method. Vibration frequencies of O-H bonds in the guests were red-shifted owing to the weakening of the O-H bonds with the formation of the complexes.     

Highly organized spherical hosts that bind organic guests in aqueous solution with micromolar affinity: microcalorimetry studies

Two novel closed-shell hemicarcerand-like hosts with spherical cavities of 11 A diameter that are soluble in aqueous solution were constructed. The binding of xylenes, aryl ethers, polyaromatic compounds, ferrocene derivatives, and bicyclic aliphatic compounds were examined by NMR spectroscopy and microcalorimetry. NMR binding studies indicated that binding depended upon guest hydrophobicity and shape. No binding was detected for guests in which a charge must be desolvated as part of inclusion or for guests that can not fit within the cavity of the host. Three complexes 2.naphthalene, 2.p-xylene, and 2.ferrocene were isolated and found to be indefinitely stable in the solid phase and in aqueous solution. The binding constants for these complexes are estimated to be greater than 10(8) M-1. Thirteen guests were examined by microcalorimetry with binding constants ranging between 10(7) and 10(3) M-1. A comparison of results obtained here with those from previous work with beta-cyclodextrin and cyclophane hosts, along with analysis of the entropy-enthalpy compensation data, indicate that there is a higher degree of guest desolvation with this host structure than with open-shell hosts. This accounts at least partially for the increase in affinity observed with these closed-shell hosts. Replacing a hydroxy group in the host portal with a hydrogen atom does not affect the binding constant, a finding consistent with the guest residing deeply buried within the host cavity. It was observed that aromatic guests are bound with higher affinity than aliphatic ones in agreement with results that point to the importance of London dispersion forces in the association of aromatic components in face-to-edge orientations. The correlation of changes in NMR chemical shift with microcalorimetry data supports a model in which increased CH-pi interactions strengthen association between host and guest due to the dominant role of van der Waals dispersion forces. Remarkably, the binding constant for the 1,4 isomer of dimethoxybenzene is 32 times higher than for the 1,2 isomer, and even greater discrimination is observed between the xylene guests since the binding constant for p-xylene is 80 times greater than that for o-xylene. This discrimination between isomeric guests by a rigid host indicates that changes in specific hydrophobic interactions have substantial effects upon binding affinity.     

Cyclodextrin dimers as receptor molecules for steroid sensors

The dansyl-modified dimer 9 complexes strongly with the steroidal bile salts. Relative to native beta-cyclodextrin, the binding of cholate (1a) and deoxycholate (1b) salts is especially enhanced. These steroids bind exclusively in a 1:1 fashion. For other bile salts (1c-1e) both 1:1 and 1:2 complexes were observed with stabilities similar to those of native beta-cyclodextrin. This indicates that only one cavity is used, with a small contribution from the second. The difference is attributed to the absence of a 12-hydroxy group in the second group of steroids. Comparison with a dimer that lacks the dansyl moiety (6) shows that this group especially hinders the cooperative binding of la and 1b. The smaller interference in the binding of the other steroids indicates that self-inclusion of the dansyl moiety hardly occurs. This weak self-inclusion is supported by fluorescence studies. The dansyl fluorescence of dimer 9 is less blue-shifted than that of other known dansyl-appended cyclodextrin derivatives; this is indicative of a more polar micro-environment. Addition of guests causes a change in fluorescence intensity.     

Complexation of Monosulfonated Triphenylphosphine with Chemically Modified β-Cyclodextrins: Effect of Substituents on the Stability of Inclusion Complexes

Interactions between the meta-substituted monosulfonated triphenylphosphine and chemically modified β-cyclodextrins were investigated in aqueous solution by NMR and UV–vis spectroscopy. Titration and continuous variation plots obtained from ³¹P NMR data indicate that the monosulfonated triphenylphosphine forms 1:1 inclusion complexes with the 2-hydroxypropylated β-cyclodextrin, the methylated β-cyclodextrin and the (2-hydroxy-3-trimethylammoniopropyl)-β-cyclodextrin chloride. These inclusion complexes are more stable that those formed with native β-cyclodextrin, confirming that poisoning of the chemically modified β-cyclodextrins by the hydrosoluble phosphine occurs when modified cyclodextrins are used as mass transfer promoters in aqueous-phase organometallic catalysis.     

Comprehensive Characterisation of the Ketoprofen-β-Cyclodextrin Inclusion Complex Using X-ray Techniques and NMR Spectroscopy

Racemic ketoprofen (KP) and β-cyclodextrin (β-CD) powder samples from co-precipitation (1), evaporation (2), and heating-under-reflux (3) were analysed using X-ray techniques and nuclear magnetic resonance (NMR) spectroscopy. On the basis of NMR studies carried out in an aqueous solution, it was found that in the samples obtained by methods 1 and 2, there were large excesses of β-CD in relation to KP, 10 and 75 times, respectively, while the sample obtained by method 3 contained equimolar amounts of β-CD and KP. NMR results indicated that KP/β-CD inclusion complexes were formed and the estimated binding constants were approximately 2400 M⁻¹, showing that KP is quite strongly associated with β-CD. On the other hand, the X-ray single-crystal technique in the solid state revealed that the (S)-KP/β-CD inclusion complex with a stoichiometry of 2:2 was obtained as a result of heating-under-reflux, for which the crystal and molecular structure were examined. Among the methods used for the preparation of the KP/β-CD complex, only method 3 is suitable.     

A Use of Modified Cyclodextrins as a Transporter for a Radiolabeled Tracer NMR Investigation

Cyclodextrins (D. Duchêne (ed.): New Trends in Cyclodextrins and Derivatives (1991)) have long been shown to be capable of modifying the water solubility of a number of hydrophobic guests through the formation of inclusion complexes. Among the three natural cyclodextrins (α, β and γ-cyclodextrins containing 6, 7 and 8 d-glucopyranose units, respectively), β-cyclodextrin is by far the most commonly used although it exhibits a weaker solubility in water (and therefore a weaker solubilization power). This specific feature has encouraged the synthesis of derivatives exhibiting an increased solubility in water. Methylated cyclodextrins are amongst the simplest derivatives, and their properties regarding the solubility and the solubilization power for hydrophobic guests are well documented especially concerning Heptakis (2,6-di-Omethyl)-cyclodextrin (DIMEB) and Heptakis (2,3,6-tri-Omethyl)-cyclodextrin (TRIMEB) K. Koizumi et al.:J. Chromatogr. 368, 329–337 (1986). In order to avoid the use of human serum albumin (HSA), this property has been applied here to the solubilization of a very sparingly water-soluble fatty acid derivative (16-iodo-3-methylhexadecanoic acid), which is known to localise in viable myocardial cells, allowing the generation of functional images reflecting the viability of the cardiac tissue through the use of radiolabeled analog (Demaison et al.: J. Nucl-Med. 29, 1230–1236 (1998)). Nuclear magnetic resonance (NMR) was used throughout this study to evidence that the observed solubilization and stabilisation (under conditions required for sterilisation) induced by cyclodextrins are due to the formation of a true inclusion complex and not to non-specific interactions; This technique further allows to derive thermodynamic as well as structural informations for this complex. On one hand, the inclusion complex prevents thermal degradation during sterilisation process compared to HSA. On the other hand, NMR displacement experiments against HSA showed that the complex likely dissociates in vivo.     

Preparation,Characterization, and Bioavailability of Host-Guest Inclusion Complex of Ginsenoside Re with Gamma-Cyclodextrin

This work aimed at improving the water solubility of Ginsenoside (G)-Re by forming an inclusion complex. The solubility parameters of G-Re in alpha (α), beta (β), and gamma (γ) cyclodextrin (CD) were investigated. The phase solubility profiles were all classified as AL-type that indicated the 1:1 stoichiometric relationship with the stability constants Ks which were 22 M⁻¹ (α-CD), 612 M⁻¹ (β-CD), and 14,410 M⁻¹ (γ-CD), respectively. Molecular docking studies confirmed the results of phase solubility with the binding energy of −4.7 (α-CD), −5.10 (β-CD), and −6.70 (γ-CD) kcal/mol, respectively. The inclusion complex (IC) of G-Re was prepared with γ-CD via the water-stirring method followed by freeze-drying. The successful preparation of IC was confirmed by powder X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In-vivo absorption studies were carried out by LC-MS/MS. Dissolution rate of G-Re was increased 9.27 times after inclusion, and the peak blood concentration was 2.7-fold higher than that of pure G-Re powder. The relative bioavailability calculated from the ratio of Area under the curve AUC₀–_∞ of the inclusion to pure G-Re powder was 171%. This study offers the first report that describes G-Re’s inclusion into γ-CD, and explored the inclusion complex’s mechanism at the molecular level. The results indicated that the solubility could be significantly improved as well as the bioavailability, implying γ-CD was a very suitable inclusion host for complex preparation of G-Re.     

Complexation of Monosulfonated Triphenylphosphine with Chemically Modified β-Cyclodextrins: Effect of Substituents on the Stability of Inclusion Complexes

Interactions between the meta-substituted monosulfonated triphenylphosphine and chemically modified β-cyclodextrins were investigated in aqueous solution by NMR and UV–vis spectroscopy. Titration and continuous variation plots obtained from ³¹P NMR data indicate that the monosulfonated triphenylphosphine forms 1:1 inclusion complexes with the 2-hydroxypropylated β-cyclodextrin, the methylated β-cyclodextrin and the (2-hydroxy-3-trimethylammoniopropyl)-β-cyclodextrin chloride. These inclusion complexes are more stable that those formed with native β-cyclodextrin, confirming that poisoning of the chemically modified β-cyclodextrins by the hydrosoluble phosphine occurs when modified cyclodextrins are used as mass transfer promoters in aqueous-phase organometallic catalysis.This revised version was published online in July 2005 with a corrected issue number.     

Host-guest complexes of a water soluble cucurbit[6]uril derivative with some dications of 1,ω-alkyldipyridines: <Superscript>1</Superscript>H NMR and X-ray structures

Interactions between a symmetrical tetramethyl-substituted cucurbit[6]uril (host: TMeQ[6]) and 1,ω-alkylenedipyridine (ω = 2, 4, 6, 8, 10) dicationic guests were investigated using ¹H NMR spectroscopy and single crystal X-ray crystallography. In these inclusion complexes, combined cavity and portal binding in TMeQ[6] were observed, and the length of the bridged alkylene was found to play an important role not only in balancing the overall hydrophilic/hydrophobic interaction between the host and the guest, but also in defining the structure of the resulting inclusion complexes. For the guest 1,2-ethylenedipyridine (Edpy), TMeQ[6] includes a positively charged pyridine ring of Edpy to form an unsymmetrical inclusion complex; for the guest 1,4-butylenedipyridine (Bdpy), TMeQ[6] includes a positively charged pyridine ring of Bdpy, but the different competitive interactions in and between the related inclusion complexes could lead to a fast exchange between the hosts and guests. For the guests with longer bridge chains, such as 1,6-hexamethylenedipyridine (Hdpy) or 1,8-octylenedipyridine (Odpy), a stable pseudorotaxane inclusion complex is formed by combining the hydrophobic cavity and the outer portal dipole-ion interactions. However, for 1,10-decatylenedipyridine (Ddpy), the two TMeQ[6] host molecules include the two end pyridine rings of Ddpy and form a dumbbell inclusion complex. Supported by the National Natural Science Foundation of China (Grant Nos. 20662003 & 20767001), the International Collaborative Project of Guizhou Province (Grant No. 2007400108), the Science Technology Fund of Guizhou Province (Grant No. J-2008-2012) and the Natural Science Youth Foundation of Guizhou University (Grant No. 2007-005)     

Interaction between tetramethylcucurbit[6]uril and some pyridine derivates

Interaction between tetramethylcucurbit[6]uril (TMeQ[6], host) with hydrochloride salts of 2-phenylpridine (G1), 2-benzylpyridine (G2), and 4-benzylpyridine (G3) (guests) have been investigated by using 1H NMR spectroscopy and electronic absorption spectroscopy and theoretical calculations. The 1H NMR spectra analysis established an interaction model in which the host selectively included the phenyl moiety of the HCl salt of the above three guests, and formed inclusion complexes with a host-guest ratio of 1:1. Absorption spectrophotometric analysis allowed quantitative measurement of the stability of these host-guest inclusion complexes. Particularly, we have established a competitive interaction in which one host-guest inclusion complex pair is much more stable than another host-guest inclusion complex pair. The stability constants for the three host-guest inclusion complexes of TMeQ[6]-G1, TMeQ[6]-G2, and TMeQ[6]-G3 are approximately 2x10(6), 60.7, and 19.9 mol-1.L, respectively. To understand how subtle differences in the structure of the title guests lead to a significant difference in the stability of the corresponding host-guest inclusion complexes with the TMeQ[6], ab initio theoretical calculations have been performed, not only for the gas phase but also the solution phase (water as solvent) in all cases. The calculation results revealed that when the phenyl moiety of the three pyridine derivate guests was included, the host-guest complexation reached the minimum, and the corresponding energy differences for the formation of the title host-guest inclusion complexes are qualitatively consistent with the experimental results.     

Inclusion Complexes of Manidipine with γ-Cyclodextrin and Identification of Photodegradation Products

The paper presents results of a study of photochemical decomposition of manidipine and its inclusion complexes with γ-cyclodextrin and identification of photodegradation products. The process was qualitatively assessed by the UV spectrophotometry and by HPLC-MS. The quantitative assessment of its efficiency was performed on the basis of kinetic parameters and quantum yields. The main product of photodegradation was nitrophenylpyridine derivative, while the concentration of nitrozophenylpyridine derivative being the other product of this process, was about 20 times lower. The inclusion complexes of manidipine with γ-cyclodextrin were obtained in the liquid phase. The stoichiometry of the complexes was determined from the Benesi–Hildebrand equation. The photochemical stability of manidipine in inclusion complexes was compared with that of manidipine in non-complexed form.This revised version was published online in July 2005 with a corrected issue number.