Crystal structure of beta-cyclodextrin-benzoic acid inclusion complex

The inclusion complex of beta-cyclodextrin (beta-CD) with benzoic acid (BA) has been characterized crystallographically. Two beta-CDs cocrystallize with two BAs, 0.7 ethanol and 20.65 water molecules [2(C(6)H(10)O(5))(7).2(C(7)H(6)O(2)).0.7(C(2)H(6)O).20.65H(2)O] in the triclinic space group P1 with unit cell constants: a=15.210(1), b=15.678(1), c=15.687(1) A, alpha=89.13(1), beta=74.64(1), gamma=76.40(1) degrees. The anisotropic refinement of 1840 atomic parameters against 16,201 X-ray diffraction data converged at R=0.078. In the crystal lattice, beta-CD forms dimers stabilized by direct O-2(m)_1/O-3(m)_1...O-2(n)_2/O-3(n)_2 hydrogen bonds (intradimer) and by indirect O-6(m)_1...,O-6(n)_2 hydrogen bonds with one or two bridging water molecules joined in between (interdimer). These dimers are stacked like coins in a roll constructing endless channels where the guest molecules are included. The BA molecules protrude with their COOH groups at the beta-CD O-6-sides and are maintained in positions by hydrogen bonding to the surrounding O-6-H groups and water molecules. Water molecules (20.65) are distributed over 30 positions in the interstices between beta-CD molecules, except the water sites W-1, W-2 that are located in the channel of the beta-CD dimer. Water site W-2 is hydrogen bonded to the disordered ethanol molecule (occupancy 0.7).     

Crystal form III of beta-cyclodextrin-ethanol inclusion complex: layer-type structure with dimeric motif

The crystal form III of the beta-cyclodextrin (beta-CD)-ethanol inclusion complex [2(C(6)H(10)O(5))(7).1.5C(2)H(5)OH.19H(2)O] belongs to the triclinic space group P1 with unit cell constants: a=15.430(1), b=15.455(1), c=17.996(1)A, alpha=99.30(1) degrees , beta=113.18(1) degrees , gamma=103.04(1) degrees . beta-CD forms dimers comprising two identical monomers that adopt a 'round' conformation stabilized by intramolecular, interglucose O-3(n)cdots, three dots, centeredO-2(n+1) hydrogen bonds. The two beta-CD monomers of form III are isostructural to that of form I in the monoclinic space group P2(1) [Steiner, T.; Mason, S. A.; Saenger, W. J. Am. Chem. Soc.1991, 113, 5676-5687], but exhibit a striking difference from that of form II in the monoclinic space group C2 [Aree, T.; Chaichit, N. Carbohydr. Res.2003, 338, 1581-1589]. The small guest EtOH molecule orients differently in the large beta-CD cavity. In form III, two disordered EtOH molecules are embedded in the beta-CD-dimer cavity. A half occupied EtOH molecule (#1) is located above the O-4 plane of beta-CD #1, whereas another doubly disordered EtOH molecule (#2, #3) is situated at about the middle of the beta-CD-dimer cavity. The three EtOH sites are maintained in positions by making van der Waals contacts to each other and to the surrounding water sites and beta-CD O-3-H group. The EtOH molecules disordered (occupancy 0.3) above the beta-CD O-4 plane in form I and fully occupied beneath the O-4 plane in form II are strongly held in positions by hydrogen bonding with the surrounding water site and beta-CD O-6-H, O-3-H groups. Occurrence of the beta-CD dimer as a structural motif of channel-type packing (form II) and layer-type packing (form III) is attributed to the higher tendency for self aggregation under the moderate acidic conditions. At weak acidic conditions, beta-CD prefers a herringbone mode (form I).     

The crystal structure of the 1:1 inclusion complex of beta-cyclodextrin with benzamide

The 1:1 inclusion complex of beta-cyclodextrin and benzamide was prepared and characterized by single crystal X-ray diffraction, PXRD, TGA, and IR. This complex crystallizes in the monoclinic P2(1) space group with unit cell constants a=15.4244(16), b=10.1574(11), c=20.557(2)A, beta=110.074(2) degrees , V=3025.1(6)A(3). The guest molecule projects into the beta-cyclodextrin cavity from the primary hydroxyl side. The amide group protrudes from the primary hydroxyl side and forms hydrogen bonds with the adjacent beta-cyclodextrin molecule. There are six crystallized water molecules, which play crucial roles in crystal packing.     

Crystal structure of cyclomaltoheptaose (beta-cyclodextrin) complexes with p-aminobenzoic acid and o-aminobenzoic acid

Crystal structures of cyclomaltoheptaose (beta-cyclodextrin) complexes with p-aminobenzoic acid and o-aminobenzoic acid have been determined by single-crystal X-ray diffraction. The space group of the beta-cyclodextrin-p-aminobenzoic acid complex is P2(1) with a host:guest stoichiometry of 1:1, and that of the beta-cyclodextrin-o-aminobenzoic acid complex is P1 with a stoichiometry of 2:3. The different structures of the guest molecules lead to the different molecular packing structures of the two complexes. Intermolecular hydrogen-bond interactions are the main force that stabilize the supramolecular systems. In both crystals, there are water molecules located near the cavity rims and in interstices between molecules of beta-cyclodextrin participating in formation of intermolecular hydrogen bonds.     

An investigation of the inclusion complex of beta-cyclodextrin with p-nitrobenzoic acid in the solid state

The weak inclusion complex of cyclomaltoheptaose (beta-cyclodextrin, betaCD) with p-nitrobenzoic acid was investigated in the solid state. Crystallography shows that two betaCD molecules co-crystallize with two p-nitrobenzoic acids and 28.5 water molecules [2(C(42)H(70)O(35))x2(C(7)H(5)NO(4))x28.5H(2)O] in the triclinic system.     

Theoretical investigations on circular and chain-like hydrogen bonded structures found in two crystal forms of α-cyclodextrin hexahydrate: Models for hydration and water clusters

Hydration of macromolecules and the structure of water of crystallization are not understood in detail because in these complex systems. H-atoms cannot be located and the hydrogen bonding schemes are not known. X-ray and neutron diffraction studies on a hydrated oligosaccharide, α-cyclodextrin 6H₂O, ((C₆H₁₀O₅)₆·6H₂O), crystals forms A and B, gave insight into the chain-like and circular arrangement of hydrogen bonds. In the circles, homodromic (unidirectional) and antidromic (counter-running) orientation of five to six hydrogen bounds is observed. PCILO calculations showed that homodromic circles and chains are approx. 8% per hydrogen bond more stable than antidromic circles, that the changes in electronic charges on H and O atoms are greater in homo than in antidromic systems and that the dipole moments are only approx. 3 D in the homodromic circles but 6–8 D in chain-like and antidromic arrangement. These results have been interpreted in terms of cooperative effect. Circular systems are considered as structural elements in hydration shells of macromolecules and in the assembly of ‘flickering’ water clusters.     

Interaction between beta-cyclodextrin and 1,10-phenanthroline: uncommon 2:3 inclusion complex in the solid state

The crystallographic structure of the complex formed by beta-cyclodextrin with 1,10-phenanthroline has been studied by X-ray diffraction. The result shows that the complex adopts an uncommon 2:3 stoichiometry in solid state, that is, every complex unit contains three 1,10-phenanthroline molecules and two beta-cyclodextrin molecules, where two 1,10-phenanthroline molecules individually occupy two cyclodextrin cavities, and the third guest molecule is located in the interstitial space between two head-to-head cyclodextrin molecules. The intermolecular hydrogen bonds between the adjacent complex units further link these individual monomers to a channel-type assembly. Furthermore, 1H and 2D NMR spectroscopy has been employed to investigate the inclusion behavior between the host beta-cyclodextrin and guest 1,10-phenanthroline in aqueous solution.     

Selective detection of uric acid in the presence of ascorbic acid at physiological pH by using a beta-cyclodextrin modified copolymer of sulfanilic acid and N-acetylaniline

A beta-cyclodextrin (CD) modified copolymer membrane of sulfanilic acid (p-ASA) and N-acetylaniline (SPNAANI) on glassy carbon electrode (GCE) was prepared and used to determine uric acid (UA) in the presence of a large excess of ascorbic acid (AA) by differential pulse voltammetry (DPV). The properties of the copolymer were characterized by X-ray photoelectron spectra (XPS) and Raman spectroscopy. The oxidation peaks of AA and UA were well separated at the composite membrane modified electrode in phosphate buffer solution (PBS, pH 7.4). A linear relationship between the peak current and the concentration of UA was obtained in the range from 1.0 x 10(-5) to 3.5 x 10(-4)mol L(-1), and the detection limit was 2.7 x 10(-6)mol L(-1) at a signal-to-noise ratio of 3. Two hundred and fifty-fold excess of AA did not interfere with the determination of UA. The application of the prepared electrode was demonstrated by measuring UA in human serum samples without any pretreatment, and the results were comparatively in agreement with the spectrometric clinical assay method.     

1H NMR studies on the hydrogen-bonding network in mono-altro-beta-cyclodextrin and its complex with adamantane-1-carboxylic acid

The hydrogen-bond network in mono-altro-beta-cyclodextrin and in its inclusion complex with adamantane-1-carboxylic acid were investigated by (1)H NMR spectroscopy using the chemical shifts, temperature coefficients and vicinal coupling constants of the exchangeable hydroxy protons. The chemical shifts of the 3-OH signals indicated that the hydrogen-bond network between the 2-OH and 3-OH groups was disturbed not only on each side of the altrose residue, but also along the whole dextrin chain. Upon addition of adamantane-1-carboxylic acid, altrose underwent a conformational change from the (1)C(4) to the (O)S(2) form, allowing a more continuous belt of hydrogen bonding, as evidenced by the downfield shift experienced by the 3-OH proton signals of the glucose residues.     

Incorporation of chlorohexidin diacetate into cotton fabrics grafted with glycidyl methacrylate and cyclodextrin

Linear electron beam radiation was used to induce grafting of glycidyl methacrylate/β-cyclodextrin mixture onto cotton fabric. Chlorohexidin diacetate was incorporated to the cavities of cyclodextrin fixed on the cotton fabric to form an inclusion complex having antimicrobial activity. After incorporating chlorohexidin diacetate, the fabric was subjected to several washing cycles to examine the durability of the antimicrobial finishing. Control and grafted cotton fabrics (before and after loading with antimicrobial agent) were characterized for their antimicrobial activity against different kinds of bacteria and fungi.Grafted fabrics loaded with antimicrobial agent were found to show good antimicrobial activity in comparison with control and grafted fabrics which are not loaded with antimicrobial agent. The grafted fabrics loaded with antimicrobial agent were found also to exhibit good antimicrobial activity after five washings and this lasting antimicrobial activity can be attributed to the inclusion complex formed between chlorohexidin diacetate molecules and the cavities of cyclodextrin.     

Successful prediction of the hydrogen bond network of the 3-oxo-12alpha-hydroxy-5beta-cholan-24-oic acid crystal from resolution of the crystal structure of deoxycholic acid and its three 3,12-dihydroxy epimers

Crystal structures of p-xylene-crystallized deoxycholic acid (3alpha,12alpha-dihydroxy-5beta-cholan-24-oic acid) and its three epimers (3beta,12alpha-; 3alpha,12beta-; and 3beta,12beta-) have been solved. Deoxycholic acid forms a crystalline (P21) complex with the solvent with a 2:1 stoichiometry whereas crystals of the three epimers do not form inclusion compounds. Crystals of the 3beta,12beta-epimer are hexagonal, whereas the 3alpha,12beta-and 3beta,12alpha-epimers crystallize in the P2(1)2(1)2(1) orthorhombic space group. The three hydrogen bond sites (two hydroxy groups, i. e. O3-H, and O12-H, and the carboxylic acid group of the side chain, O24bO24a-H) simultaneously act as hydrogen bond donors and acceptors. The hydrogen bond network in the crystals was analyzed and the following sequences have been observed: two chains (abcabc... or acbacb... ) and two rings (abc or acb), which constitute a complete set of all the possible sequences which can be drawn for an intermolecular hydrogen bond network formed by three hydrogen bond donor/acceptor sites forming crossing hydrogen bonds. The orientation of O3-H (alpha or beta) determines the sequence of the acceptor and the donor groups involved in the pattern: O24a --> O12 --> O3 --> O24b when it is alpha and O24a --> O3 --> O12--> O24B when it is beta. These observations were used to predict the hydrogen bond network of p-xylene-crystallized 3-oxo,12alpha-hydroxy-5beta-cholan-24-oic acid. This compound has two hydrogen bond donor and three potential hydrogen bond acceptor sites. According to the previous sequence set, this compound should crystallize in the monoclinic P21 system, should form a complex with the solvent, O24b should not participate in the hydrogen bond network, and the chain sequence O24a --> O12 --> O3 would be followed. All predictions were confirmed experimentally.     

Formation of a supramolecular ladder using dinuclear dicyanamide bridged Cu(II) species: Synthesis, crystal structure and magnetic property

The reaction of Cu(ClO₄)₂ · 6H₂O with bis(3-aminopropyl)methylamine and sodium dicyanamide in aqueous medium results in the formation of a dimeric dicyanamide complex of Cu(II), [Cu₂(medpt)₂(dca)₂](ClO₄)₂. The single crystal X-ray structure reveals that the dinuclear entities are extended to form a supramolecular 1D ladder by H-bonding. Each dinuclear entity is joined to the adjacent unit via the perchlorate anion. Variable temperature magnetic study was performed and the best-fit parameters are J = −1.20 ± 0.02 cm⁻¹, g = 2.08 ± 0.01 with R = 2 × 10⁻⁵. These clearly indicate the antiferromagnetic interaction between the Cu(II) center.     

A novel approach to predicting protein structural classes in a (20–1)-D amino acid composition space

The development of prediction methods based on statistical theory generally consists of two parts: one is focused on the exploration of new algorithms, and the other on the improvement of a training database. The current study is devoted to improving the prediction of protein structural classes from both of the two aspects. To explore a new algorithm, a method has been developed that makes allowance for taking into account the coupling effect among different amino acid components of a protein by a covariance matrix. To improve the training database, the selection of proteins is carried out so that they have (1) as many non-homologous structures as possible, and (2) a good quality of structure. Thus, 129 representative proteins are selected. They are classified into 30 α, 30 β, 30 α + β, 30 α/β, and 9 ζ (irregular) proteins according to a new criterion that better reflects the feature of the structural classes concerned. The average accuracy of prediction by the current method for the 4 × 30 regular proteins is 99.2%, and that for 64 independent testing proteins not included in the training database is 95.3%. To further validate its efficiency, a jackknife analysis has been performed for the current method as well as the previous ones, and the results are also much in favor of the current method. To complete the mathematical basis, a theorem is presented and proved in Appendix A that is instructive for understanding the novel method at a deeper level. © 1995 Wiley-Liss, Inc.     

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

From humble beginnings of a contaminated petri dish, β‐lactam antibiotics have distinguished themselves among some of the most powerful drugs in human history. The devastating effects of antibiotic resistance have nevertheless led to an “arms race” with disquieting prospects. The emergence of multidrug resistant bacteria threatens an ever‐dwindling antibiotic arsenal, calling for new discovery, rediscovery, and innovation in β‐lactam research. Here the current state of β‐lactam antibiotics from a structural perspective was reviewed.     

Determination of urinary 18β-glycyrrhetinic acid by gas chromatography and its clinical application in man

A sensitive and quantitative gas chromatographic assay for the determination of 18β-glycyrrhetinic acid (18β-GA), the main metabolite of glycyrrhizin after oral licorice consumption in human urine, has been developed and validated. For the extraction of 18β-GA from urine two Sep-Pak C₁₈ extractions, hydrolysis with Helix pomatia and three liquid–liquid extractions were performed, using 18α-glycyrrhetinic acid (18α-GA) as internal standard. Both 18β-GA and internal standard were converted into their pentafluorobenzyl-ester/trimethylsilyl-ether derivatives and detected by flame ionization detection using a WCOT-fused-silica capillary column. Good quality control data were obtained in precision and accuracy tests. The detection limit of the gas chromatographic method was 10 μg/l with a urine volume of 10 ml. A detection limit of 3 μg/l was obtained by performing GC–MS. The GC method was used to monitor the urinary excretion of 18β-GA after licorice consumption by two healthy volunteers and a patient suspected of licorice abuse. Furthermore, it was shown that this GC assay enables to detect other metabolites related to licorice consumption.     

Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARalpha/gamma dual agonists, and X-ray crystallographic studies

A new series of α-aryl or α-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARα and PPARγ was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARγ-ligand-binding domain was obtained and discussed in this report.     

Neutron scattering shows a droplet of oleic acid at the center of the BAMLET complex

The anti‐cancer complex, Bovine Alpha‐lactalbumin Made LEthal to Tumors (BAMLET), has intriguing broad‐spectrum anti‐cancer activity. Although aspects of BAMLET's anti‐cancer mechanism are still not known, it is understood that it involves the oleic acid or oleate component of BAMLET being preferentially released into cancer cell membranes leading to increased membrane permeability and lysis. The structure of the protein component of BAMLET has previously been elucidated by small angle X‐ray scattering (SAXS) to be partially unfolded and dramatically enlarged. However, the structure of the oleic acid component of BAMLET and its disposition with respect to the protein component was not revealed as oleic acid has the same X‐ray scattering length density (SLD) as water. Employing the difference in the neutron SLDs of hydrogen and deuterium, we carried out solvent contrast variation small angle neutron scattering (SANS) experiments of hydrogenated BAMLET in deuterated water buffers, to reveal the size, shape, and disposition of the oleic acid component of BAMLET. Our resulting analysis and models generated from SANS and SAXS data indicate that oleic acid forms a spherical droplet of oil incompletely encapsulated by the partially unfolded protein component. This model provides insight into the anti‐cancer mechanism of this cache of lipid. The model also reveals a protein component “tail” not associated with the oleic acid component that is able to interact with the tail of other BAMLET molecules, providing a plausible explanation of how BAMLET readily forms aggregates. Proteins 2017; 85:1371–1378. © 2017 Wiley Periodicals, Inc.     

Solubility enhancement of mefenamic acid by inclusion complex with β-cyclodextrin: in silico modelling,formulation, characterisation,and in vitro studies

The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with β-cyclodextrin (β-CD). First, the phase solubility diagram of MA in β-CD was drawn from 0 to 21 × 10⁻³ M of β-CD concentration. A job’s plot experiment was used to determine the stoichiometry of the MA:β-CD complex (2:1). The stability of this complex was confirmed by molecular modelling simulation. Three methods, namely solvent co-evaporation (CE), kneading (KN), and physical mixture (PM), were used to prepare the (2:1) MA:β-CD complexes. All complexes were fully characterised. The drug dissolution tests were established in simulated liquid gastric and the MA water solubility at pH 1.2 from complexes was significantly improved. The mechanism of MA released from the β-CD complexes was illustrated through a mathematical treatment. Finally, two in vitro experiments confirmed the interest to use a (2:1) MA:β-CD complex.     

Racemization and hydrolysis of tropic acid alkaloids in the presence of cyclodextrins

Because of the constantly increasing demand for optically pure drugs it is of great importance to elucidate factors affecting stereochemistry, in order to provide a stable formulation with a high chiral quality of the desired isomer. Therefore, the effects of cyclodextrins (CyDs) and their alkylated and hydroxyalkylated derivatives on racemization and hydrolysis of (?)-(S)-hyoscyamine and (?)-(S)-scopolamine were examined kinetically and spectroscopically (NMR). Direct methods, based on a chiral and achiral chromatographic phase system, were used to determine their degradation products and enantiomer composition during stability tests. All different CyDs, except α-CyD, retarded racemization and hydrolysis. The inclusion of the drug substances in CyDs inhibits the attack of hydroxyl ions and/or water molecules and thus retards the racemization and hydrolysis. The racemization of the tropic acid alkaloids is dependent on the pH and temperature. NMR studies were used to evidence the formation of a soluble 1:1 complex in aqueous solution. © 1993 Wiley-Liss, Inc.