Mechanochemical Complexation between Deoxycholic Acid and Salicylic Acid

A complex between deoxycholic acid (DCA) and salicylic acid (SA) was prepared by grinding and coprecipitation methods. The resultant complex was characterized by means of powder X-ray diffractometry, IR spectroscopy and thermal analysis. The stoichiometry (DCA : SA 1 : 1) of the complex obtained by grinding was identical to that obtained by coprecipitation. The powder X-ray diffraction pattern of the DCA–SA complex differed from the typical pattern of DCA–guest complexes such as DCA–camphor and DCA–phenanthrene complexes. IR spectra suggested that a different kind of hydrogen bonding was formed in the crystal of the DCA–SA complex, compared with the other DCA–guest complexes. This was in good agreement with data from the crystal structure.     

8-oxoguanine lesioned B-DNA molecule complexed with repair enzyme hOGG1: a molecular dynamics study

The molecular dynamics (MD) simulation of DNA mutagenic oxidative lesion, 7,8-dihydro-8-oxoguanine (8-oxoG), complexed with the repair enzyme, human oxoguanine glycosylase 1 (hOGG1), was performed for 1 nanosecond (ns) in order to describe the dynamical process of DNA-enzyme complex formation. After 900 picoseconds of MD the lesioned DNA and enzyme formed a complex that lasted until the end of the simulation at 1 ns. The complex was mainly represented by the overlapping van der Waals surfaces of DNA and enzyme molecules. The amino group of arginine 324 was located close to the phosphodiester bond of the nucleotide with 8-oxoG enabling chemical reactions between amino acid and lesion. The broken hydrogen bonds resulting in locally collapsed B-DNA structure were observed at the lesion site. The phosphodiester bond at C5' of 8-oxoG was displaced to the position close to the amino group of arginine 324. The water-mediated hydrogen bond network was formed in each contact area between DNA and enzyme, further enhancing the stability of the complex. In the background simulation of the identical molecular system with the native DNA, neither the complex nor the water- mediated hydrogen bond network was observed.     

Determination of related impurities of bile acids in bulk drugs by cyclodextrin-modified micellar electrokinetic chromatography

A cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) method has been developed and validated for purity determination of two bile acids, ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA). Quantitation of related impurities such as lithocholic acid (LCA), chenodeoxycholic acid (CDCA), cholic acid (CA), and DCA in UDCA and CA in DCA was performed. A running buffer containing 20 mM borate-phosphate, 50 mM sodium dodecyl sulfate (SDS), 2.0 mM beta-cyclodextrin, and acetonitrile was used. Modifiers were added to improve resolution and selectivity. The applied voltage was 25 kV and detection was performed at 185 nm. Validation parameters such as selectivity, linearity, repeatability, intermediate precision, limit of detection, limit of quantitation, and robustness were evaluated. The method was simple and proved to be useful for the purity testing of bile acids in bulk drugs. Good results were obtained for related impurities at concentration levels from 0.05 to 1.5% with respect to the main component, according to international requirements.     

Encapsulation of dicinnamalacetone in β-cyclodextrin: A physicochemical evaluation and molecular modeling approach on 1:2 inclusion complex

The aim of this research is to prepare and characterize the inclusion complex between Dicinnamalacetone (DCA) and β-CD. The inclusion complex of Dicinnamalacetone [DCA] and Beta-cyclodextrin [β-CD] was characterized both in solution and solid state by UV-visible spectroscopy, Fluorescence spectroscopy, Nano second time resolved fluorescence study, Fourier Transform Infra-red spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), Powder X-ray diffractometry (XRD), Atomic Force Microscopy (AFM) and molecular modeling test. The 1:2 soichiometry of inclusion complex and binding constant values were determined by Benesi-Hildebrand plot and confirmed by Job's continuous variation method. FT-IR study indicated that the aromatic rings of the Dicinnamalacetone molecule were included in the β-CD cavities. The nano second time resolved fluorescence study revealed that DCA exhibits single exponential decay in aqueous medium and bi-exponential decay in β-CD medium indicating the formation of inclusion complex. From the DSC study it is observed that the thermal stability of the inclusion complex was significantly enhanced when compared with the pure compound due to strong interaction between DCA and β-CD. Furthermore, implementation of molecular modeling test confirmed that the complexation could reduce the energy of the system. The experimental studies revealed that the most predominant structure of 1:2 inclusion complex is the one in which the two aromatic ends of DCA were inserted into the cavities of two β-CD molecules.     

Elucidation of solid-state complexation in ground mixtures of cholic acid and guest compounds

The solid-state complexation between cholic acid (CA) and either methyl p-hydroxybenzoate (MPB) or ibuprofen (IBP) was investigated. Powder X-ray diffractometry, IR spectroscopy and thermal analysis suggested the complex formation between CA and MPB as well as between CA and IBP by co-grinding method. The stoichiometry of CA-MPB was 1 : 1 while that of CA-IBP was 2 : 1, reflecting the effect of guest size on complex formation. The guest compounds were assumed to be included in the channel of complexes formed by hydrogen bonds among CA molecules.     

Determination of bile acids in pig liver, pig kidney and bovine liver by gas chromatography-chemical ionization tandem mass spectrometry with total ion chromatograms and extraction ion chromatograms

An effective method has been developed for quantitative determination of six bile acids including lithocholic acid (LCA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), hydodeoxycholic acid (HDCA), cholic acid (CA) and ursodeoxycholic acid (UDCA) in biological tissues including pig liver, pig kidney and bovine liver by gas chromatography-chemical ionization/tandem mass spectrometry (GC-CI/MS/MS). Camphor-10-sulphonic acid (CSA) was proposed as effective catalyst for bile acid derivatization. Reactions were accelerated ultrasonically. The effects of different catalysts and reaction times on derivatization efficiency were evaluated and optimized. Bile acids were determined as methyl ester-trimethylsilyl ether and methyl ester-acetate derivatives. The efficiency of trimethylsilylation and acetylation was evaluated. Trimethylsilylation was done with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) as the trimethylsilyl donating reagent in a ultrasonic bath for 20 min. Acetylation was done in pyridine with acetic anhydride at 40-45°C for 4 h. The former reaction was faster than the latter. Thus, trimethylsilylation was employed for the quantitative analysis. Negligible interferences from sterols in biological matrices were observed when the biological samples were treated with solid phase extraction before GC-CI/MS/MS. The linearity, reproducibility, detection limit and recovery were evaluated under the optimized conditions. Satisfactory results were obtained when bile acid derivatives of LCA, CDCA, HDCA, and UDCA were determined with total ion chromatograms (TIC) while DCA and CA were determined with extracted ion chromatograms (EIC), respectively. The detection limits (S/N=3) for six bile acids in biological tissues were ranging from 0.40 to 1.6 ng/mL and the recoveries indicated that the proposed method was feasible for the determination of trace bile acids in the biological samples studied. The experimental results for the animal tissues purchased from five different markets were compared. Interestingly, all of the six bile acids were present in pig liver while only the dihydroxy bile acids, DCA, CDCA and HDCA were found in pig kidney. In addition to DCA and CDCA, trihydroxy bile acid, CA, are the major bile acids in bovine liver.     

包结聚合

本文主要叙述以脱胆酸(DCA)为包结体的包结聚合的研究历史。各种烯类单体、双烯、环状双烯、双炔、氯代丙烯腈等聚合单体在DCA管道中的包结聚合行为及不对称包结聚合。     

A New Functional Cyclophane Host. Synthesis, Complex Formation and Crystal Structures of Three Inclusion Compounds

A new macrocyclic host compound 2 having an octamethylsubstituted cyclophane structure with two intra-annular carboxylic acid functions has beensynthesized. The properties of crystalline inclusion formation are studied and X-ray crystalstructures of three inclusion complexes including acetic acid, propionic acid and acetone asthe guest molecules are reported. Inter-host channel formation with complexed guest moleculesaccommodated into the channels are typical features of the acetic acid and acetone 1 : 4 (host : guest) stoichiometric complexes being also hydrated species, while the propionicacid 1 : 2 complex is of the close packing type containing no additional water molecules.Systems of hydrogen bonds involving the host and guest functional groups are common toall structures. In the case of the acetic acid inclusion compound, a complex supramolecularhydrogen-bonded array comprising a bordering tricyclic assembly of eight molecular species exists.     

Experimental and theoretical charge density distribution in a host-guest system: synthetic terephthaloyl receptor complexed to adipic acid

The experimental charge density distributions in a host-guest complex have been determined. The host, 1,4-bis[[(6-methylpyrid-2-yl)amino]carbonyl]benzene (1) and guest, adipic acid (2). The molecular geometries of 1 and 2 are controlled by the presence in the complex of intermolecular hydrogen bonding interactions and the presence in the host 1 of intramolecular hydrogen bonding motifs. This system therefore serves as an excellent model for studying noncovalent interactions and their effects on structure and electron density, and the transferability of electron distribution properties between closely related molecules. For the complex, high resolution X-ray diffraction data created the basis for a charge density refinement using a pseudoatomic multipolar expansion (Hansen-Coppens formalism) against extensive low-temperature (T = 100 K) single-crystal X-ray diffraction data and compared with a selection of theoretical DFT calculations on the same complex. The molecules crystallize in the noncentrosymmetric space group P2(1)2(1)2(1) with two independent molecules in the asymmetric unit. A topological analysis of the resulting density distribution using the atoms in molecules methodology is presented along with multipole populations, showing that the host and guest structures are relatively unaltered by the geometry changes on complexation. Three separate refinement protocols were adopted to determine the effects of the inclusion of calculated hydrogen atom anisotropic displacement parameters on hydrogen bond strengths. For the isotropic model, the total hydrogen bond energy differs from the DFT calculated value by ca. 70 kJ mol(-1), whereas the inclusion of higher multipole expansion levels on anisotropic hydrogen atoms this difference is reduced to ca. 20 kJ mol(-l), highlighting the usefulness of this protocol when describing H-bond energetics.     

Enantioselective inclusion of (R)-phenylglycyl-(R)-phenylglycine with benzyl methyl sulfoxides

A crystalline dipeptide, (R)-phenylglycyl-(R)-phenylglycine (RR-1), recognized p-halobenzyl methyl sulfoxides with high R-enantioselectivity (86–99% ee) to form inclusion compounds. The single-crystal X-ray analyses showed that RR-1 molecules are arranged in parallel and zigzags via hydrogen bonding to construct a pleated sheet. The guest molecules that form hydrogen bond with ⁺NH₃ of RR-1 are accommodated in the channel cavity between the layers. In contrast to the inclusion crystals of parent benzyl methyl sulfoxide, in which a rectangular cavity is formed, the cavity including p-halobenzyl methyl sulfoxides becomes rhomboidal. We also examine the guest exchange in these inclusion compounds and it was found that the guest exchanges occur when the host structure changes.     

Determination of the structure of quinolone-γ-cyclodextrin complexes and their binding constants by means of UV–Vis and <Superscript>1</Superscript>H NMR

The host–guest inclusion complex structure and binding ability of two different quinolones with γ-cyclodextrin (γ-CD) were investigated in solution by means of UV–Vis and ¹H NMR spectroscopy. Competition of oxolinic and nalidixic acid molecules for the γ-CD cavity was evaluated by determination of association constants. Both quinolones form 1:1 inclusion complexes, their binding constants at room temperature (25 °C) under acidic and basic conditions were calculated using Benesi–Hildebrand equation. The stability of the complexes was dependent on the structure of the quinolone. In general, the weaker binding constants were observed for oxolinic acid-γ-CD complexes (1616 and 1765 M^?1) and the larger binding constants were obtained for nalidixic acid-γ-CD complexes (3760 and 3840 M^?1). ¹H NMR studies in D₂O were performed to elucidate the structure of each inclusion complex, nalidixic acid molecule penetrates more deeply into the γ-CD cavity and an intermolecular hydrogen bond is formed. Knowledge about structure and relative stability of quinolone-γ-CD complexes will be useful for future applications of these antimicrobial agents in medicinal chemistry.     

In situ observation of the four-step dehydration process of the 1 beta-methylcarbapenem antibiotic CS-834 crystal by X-rays

The 1 beta-methylcarbapenem antibiotic CS-834 takes six crystalline forms depending on ambient conditions. The X-ray powder diffraction revealed that the dihydrate crystal (B2-form) was changed to the monohydrate (B1-form) through the intermediate form (B2'-form). The monohydrate form was then changed to the dehydrate (B0-form) through the intermediate B1'-form. The progress of the dehydration along the needle axis (c-axis) was observed under a microscope. When a single crystal of the B2-form was mounted on a diffractometer and the humidity was reduced, the crystal was gradually changed to the various dehydration forms with retention of the single crystal. The crystals of B2- to B0-forms form isostructures to each other except the solvent water molecules. In the crystal structure of the B1-form, the pivaloyloxymethyl moiety is disordered. One is nearly similar to that of the B2-form, while another is similar to that of the B0-form. Each crystal structure consists of a columnar arrangement of CS-834 along the c-axis, and the water molecules are located between the columns and form a characteristic hydrogen bond network. When the water molecules leave the crystal, the columns slide slightly following the slight conformational change in the pivaloyloxymethyl groups and are connected by another type of hydrogen bond network. Such a rearrangement of the hydrogen bond network should be a motive force of the phase change to the next step due to the dehydration. Since the hydrogen bond network extends along the c-axis, the dehydration proceeds along the c-axis as observed microscopically.     

Investigating the proton transferring route in a heteroaromatic compound part I: a trial to develop di- and trifunctional benzimidazole model compounds inducing the molecular packing structure with a hydrogen bond network

Di- and trifunctional benzimidazole molecules, 1 and 2, have been synthesized as the model compounds to identify their molecular packing structure and hydrogen bond network, which is possibly involved in the proton transfer system belonging to its heteroaromatic functional groups. By carrying out the simple reaction between acid chloride and diamine, the desired benzimidazole model compounds are obtained with high yield above 60%. The comparison studies between the model compounds and benzimidazole reveal that the model compounds show well-packing structure with intermolecular hydrogen bonds similar to those observed in benzimidazole. The presence of solvent with 2 leads to the unique intermolecular hydrogen bonds between one molecule of 2 and six molecules of solvent (i.e., 2-propanol) resulting in the solvent-assisted intramolecular hydrogen bond network among benzimidazole functional groups. The comparative studies of the effect of temperature on the packing structure and hydrogen bond in the model compounds indicate that the development of the benzimidazole unit from monofunctional to difunctional and finally trifunctional enhances the intermolecular interaction between the molecules and results in the stronger molecular packing structure of the compounds. A study on proton conductivity by preparing the sulfonated poly(ether ether ketone) (SPEEK) membranes with benzimidazole, 1, and 2 for 15 phr equivalent to benzimidazole group clarifies (i) incorporation of benzimidazole compounds improves the proton conductivity of SPEEK in dry condition and (ii) the increase in proton conductivity is relevant to the number of benzimidazole group on molecule.     

Stereological simulations of asymmetric polymerization in channels of bile acid inclusion compounds: A detailed analysis of the monomer arrangements in the channels

We studied simulations by computer graphics to estimate the steric mechanism of the asymmetric polymerization of prochiral diene monomers in channels of inclusion compounds of steroidal bile acids, such as deoxycholic acid (DCA) and cholic acid. We applied a hierarchization method to interpret the crystal structures of bile acids, clarifying that the chiral host molecules associated to form characteristic 2₁-helical assemblies with uneven surfaces. A detailed analysis of the uneven channels in a close-packing state indicated that there were many possible arrangements of the monomers in the channels. The plausible arrangements in the channel could explain a previous study, which showed that the polymerization in the DCA channel yielded chiral polymers with a predominant configuration from prochiral diene monomers, such as 2-methyl-trans-1,3-pentadiene. On the basis of such simulation studies of the arrangements of guest monomers in the channel, we examined a plausible steric mechanism for asymmetric inclusion polymerization. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4648–4655, 2004     

Dimensionality control of vapochromic hydrogen-bonded proton-transfer assemblies composed of a bis(hydrazone)iron(II) complex

We describe the novel synthesis of a bis(hydrazone)iron(II) complex in protonated [Fe(Hpbph)(2)]Cl(2) (1) and deprotonated [Fe(pbph)(2)] (2) forms and several hydrogen-bonded proton-transfer (HBPT) assemblies having different dimensionalities of hydrogen-bonded network structures, [Fe(Hpbph)(2)](CA)·2CH(3)OH (3), [Fe(Hpbph)(2)](HCA)(2)·2THF (4), and [Fe(Hpbph)(2)](CA)(H(2)CA)(2)·2CH(3)CN (5) (Hpbph = 2-(diphenylphosphino)benzaldehyde-2-pyridylhydrazone), consisting of a deprotonated Fe(II)-hydrazone complex (2) as a proton acceptor (A) and chloranilic acid (H(2)CA) as a proton donor (D). The deprotonated complex 2 exhibited two-step reversible protonation reactions to form the double-protonated form 1, and the acid-dissociation constants were determined to be 7.6 and 10.3 in methanol solution. Utilizing this proton-accepting ability of 2, we succeeded in synthesizing HBPT assemblies 3, 4, and 5 from the reactions in CH(3)OH, THF, and CH(3)CN, respectively, with the same D/A ratio of H(2)CA/[Fe(pbph)(2)] = 10:1. These assemblies were found to have one-dimensional (1-D), two-dimensional (2-D), and three-dimensional (3-D) hydrogen-bonded networks with D/A ratios of 1:1, 2:1, and 3:1 for 3, 4, and 5, respectively. In 3, a 1-D hydrogen-bonded chain composed of the alternate arrangement of [Fe(Hpbph)(2)](2+) and CA(2-), {···[Fe(Hpbph)(2)](2+)···CA(2-)···}(∞), was surrounded by solvated methanol molecules to form isolated 1-D hydrogen-bonded chains. In the HBPT assembly 4, a 2-D hydrogen-bonded sheet was formed from two types of hydrogen-bonded chains, {···[Fe(Hpbph)(2)](2+)···HCA(-)···HCA(-)···}(∞) and {···HCA(-)···HCA(-)···}(∞), and solvated THF molecules did not form any hydrogen bonds. In 5, two orthogonal hydrogen-bonded chains constructed from the neutral chloranilic acid molecules, {···CA(2-)···2(H(2)CA)···}(∞), were formed in addition to the 1-D hydrogen-bonded chain similar to that in 3, resulting in the formation of a rigid 3-D hydrogen-bonded network structure. By controlling the dimensionality of the hydrogen bond network, we found that the 2-D HBPT assembly 4 is sufficiently flexible to exhibit interesting vapochromic behavior in response to various organic vapors.     

Effect of n-alkyl chain length on the complexation of phenanthrene and 9-alkyl-phenanthrene with beta-cyclodextrin

The characteristics of host-guest complexation between beta-cyclodextrin (beta-CD) and phenanthrene derivatives (phenanthrene, n-propyl, n-butyl and n-hexyl-phenanthrene) were investigated by fluorescence spectrometry. Linear and non-linear regression methods were used to estimate the formation constants (K1). A 1:1 stoichiometric ratio and an effect of n-alkyl chain length on the formation constant were observed for the binary inclusion complex between guest and beta-CD. The formation constant dramatically increases with the length of n-alkyl, it starts from the value of 140 l mol(-1) for the phenanthrene to reach the value of 580 l mol(-1) for hexyl-phenanthrene. The effect of the temperature on the fluorescence intensity of each complex (guest-host) was also studied; and then the thermodynamic parameters were calculated. The main inclusion site seems to be aromatic moiety for short chain molecules, and it moves toward the alkyl chain part, as the chain becomes longer.     

Determination of bile acids in serum and bile by a modified gas chromatographic glass capillary technique

Summary A modified gas chromatographic glass capillary technique for determination of five major bile acids (Cholic acid: CA, Chenodeoxycholic acid: CDCA, Deoxycholic acid: DCA, Lithocholic acid: LCA and Ursodeoxycholic acid: UDCA) has been developed after preliminary extraction with XAD-2 resin. Enzymatic hydrolysis prevents the formation of interferring degradation products. Ether extraction with centrifugation eliminates water soluble interferring substances. Derivatization to hexafluorpropyl- instead of methyl esters results in better separation, shortens analysis time and prolongs the life span of the column.     

Synthesis of 2-pyridone-fused 2,2'-bipyridine derivatives. An unexpectedly complex solid state structure of 3,6-dimethyl-9H-4,5,9-triazaphenanthren-10-one

2-Pyridone-fused 2,2'-bipyridine derivatives and were synthesised. X-Ray diffraction analysis of revealed a highly complex solid state structure with a disordered molecule imbedded in a channel structure formed by a centrosymmetric lattice of hexagonally packed, hydrogen bonded columns. The columns are assembled from three symmetry independent molecules. Dimerisation of the self-complementary cis-amide hydrogen bond motif is overridden by the fulfilment of the proton coordination ability of the phenanthroline nitrogens in accordance with Etter's rules of hydrogen bond priorities.     

Polymorphism of Inclusion Complexes and Unsolvated Hosts. III. Dimorphism of the Alkaloid Colchicine Hydrate. The Structure of Colchicine Monohydrate

The alkaloid colchicine forms, in addition to the previously known dihydrate host–guest complex, a monohydrate complex. The crystal structure of the monohydrate was determined by direct methods and refined to a final R value of 0.046 for 1425 observed reflections. Crystal data are: orthorhombic, space group P2 12 12 1, a = 9.145(2) Å; b = 13.270(3) Å; c = 17.942(4) Å, V = 2177(1) Å3, Z= 4, Dx = 1.22 g cm-3, T = 293 K. The conformation of the molecule is practically identical with the conformation in the dihydrate inclusion complex. Water molecules show proton donor as well as proton acceptor properties and are hydrogen bonded with the three colchicine molecules giving rise to the three dimensional H-bonded network.     

First principles molecular dynamics study of filled ice hydrogen hydrate

We investigated structural changes, phase diagram, and vibrational properties of hydrogen hydrate in filled-ice phase C(2) by using first principles molecular dynamics simulation. It was found that the experimentally reported "cubic" structure is unstable at low temperature and∕or high pressure: The "cubic" structure reflects the symmetry at high (room) temperature where the hydrogen bond network is disordered and the hydrogen molecules are orientationally disordered due to thermal rotation. In this sense, the "cubic" symmetry would definitely be lowered at low temperature where the hydrogen bond network and the hydrogen molecules are expected to be ordered. At room temperature and below 30 GPa, it is the thermal effects that play an essential role in stabilizing the structure in "cubic" symmetry. Above 60 GPa, the hydrogen bonds in the framework would be symmetrized and the hydrogen bond order-disorder transition would disappear. These results also suggest the phase behavior of other filled-ice hydrates. In the case of rare gas hydrate, there would be no guest molecules' rotation-nonrotation transition since the guest molecules keep their spherical symmetry at any temperature. On the contrary methane hydrate MH-III would show complex transitions due to the lower symmetry of the guest molecule. These results would encourage further experimental studies, especially nuclear magnetic resonance spectroscopy and neutron scattering, on the phases of filled-ice hydrates at high pressures and∕or low temperatures.