Application of the Prigogine-Flory-Patterson theory part III. Mixtures of a bicyclic compound,benzene, cyclohexane,n-hexane with a cycloalkane,cyclohexene, a cycloalkadiene and benzene

The Prigogine-Flory-Patterson theory of liquid mixtures has been qpplied to the H _m ^E and V _m ^E for binary mixtures of a bicyclic compound, benzene, cyclohexane and n-hexane with a cycloalkane, cyclohexene, a cycloalkadiene and benzene. Furthermore the Prigogine-Flory theory has been used to predict activity coefficients at infinite dilution from the experimentally determined H _m ^E at 25°C for the mixtures cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene and benzene with a bicyclic compound. The predictions are compared to experimental results.     

New approach to molecular docking and its application to virtual screening of chemical databases

This paper describes the validation of a molecular docking method and its application to virtual database screening. The code flexibly docks ligand molecules into rigid receptor structures using a tabu search methodology driven by an empirically derived function for estimating the binding affinity of a protein-ligand complex. The docking method has been tested on 70 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. The lowest energy geometry produced by the docking protocol is within 2.0 A root mean square of the experimental binding mode for 79% of the complexes. The method has been applied to the problem of virtual database screening to identify known ligands for thrombin, factor Xa, and the estrogen receptor. A database of 10,000 randomly chosen "druglike" molecules has been docked into the three receptor structures. In each case known receptor ligands were included in the study. The results showed good separation between the predicted binding affinities of the known ligand set and the database subset.     

Oriented crystalline monolayers and bilayers of 2 x 2 silver(I) grid architectures at the air-solution interface: their assembly and crystal structure elucidation

Oriented crystalline monolayers, approximately 14 A thick, of a 2 x 2 Ag+ grid complex, self-assembled at the air-solution interface starting from an water-insoluble ligand 3,6-bis[2-(6-phenylpyridine)]pyridazine spread on silver-ion-containing solutions, were examined by grazing-incidence X-ray diffraction and specular X-ray reflectivity using synchrotron radiation. The monolayer structure was refined, including a determination of the positions of the counter-ions, with the SHELX-97 computer program. The monolayers were transferred from the interface onto various solid supports and visualized by scanning force microscopy, and characterized by X-ray photoelectron spectroscopy in terms of molecular structure. On surface compression, the initial self-assembled monolayer undergoes a transition to a crystalline bilayer in which the two layers, almost retaining the original arrangement, are in registry. Such a phase transition is of relevance to the understanding of crystal nucleation.     

Detection of streptomycin and dihydrostreptomycin residues in milk,honey and meat samples using an optical biosensor

Immuno-biosensor inhibition assays for the detection of streptomycin and dihydrostreptomycin residues in whole cows' milk, honey, pig kidney and pig muscle are reported. The antibody showed high cross-reactivity with dihydrostreptomycin in various foodstuffs (buffer 103%, milk 96%, honey 84%, kidney extract 129% and muscle extract 98%). There was no significant cross-reaction with other aminoglycosides or commonly used antibiotics. A streptomycin derivative was used to prepare a stable, reusable sensor chip surface. The assay allowed the direct analysis of bovine whole milk (fat content approximately 3.5%). Honey samples required dilution with buffer, while kidney and muscle samples from pigs were homogenized in an aqueous extraction buffer and clarified by centrifugation. The limit of detection for each assay was determined from known streptomycin-free samples (n = 20; mean - (3 x standard deviation)) and the results were as follows: milk 30 microg kg(-1), honey 15 microg kg(-1), kidney 50 microg kg(-1) and muscle 70 microg kg(-1). Repeatability (or relative standard deviation) between runs were calculated (n = 3) at the respective Community maximum residue limits (MRL) and 0.5 x MRL with the exception of honey since no European MRL exists at present. Results were determined as 4.3% (200 microg kg(-1)) and 2.8% (100 microg kg(-1)) in milk, 13.3% (40 microg kg(-1)) and 9.5% (20 microg kg(-1)) in honey, 7.1% (1000 microg kg(-1)) and 7.6% (500 microg kg(-1)) in kidney and 7.1% (500 microg kg(-1)) and 11% (250 microg kg(-1)) in muscle.     

Simplified method for the Re-Os dating of molybdenite using acid digestion and isotope dilution ICP-MS

An analytical method was developed for Os-Re dating of molybdenite. The method is based on determination of Os and Re concentrations in molybdenite by isotope dilution inductively-coupled plasma mass spectrometry (ID-ICP-MS). Sample digestion and sample/spike equilibration were achieved by a two-stage autoclave-based procedure using a mixture of nitric and sulphuric acids. Os was separated from the sample digest by modified single-stage distillation of osmium tetraoxide (OsO₄) using elevated temperature and on-line addition of hydrogen peroxide. OsO₄(g) was trapped in a mixture of 0.05% thiourea in 0.05 M sodium hydroxide. An anion-exchange column was used to separate Re from excess Mo in the solution remaining after distillation. Os and Re isotope ratio measurements were performed by single-collector, double focusing inductively-coupled plasma mass spectrometry (ICP-MS) with on-line mass-bias correction. Typical instrumental precision was in the range 0.02-0.2% relative standard deviation (R.S.D.) depending on the analyte concentrations. Notorious Os memory effects in the ICP-MS introduction system were eliminated using 5% ammonia solution, both as matrix for final dilution of the trap mixture as well as for washing between the samples. The reproducibility of the entire analytical procedure was accessed by replicate dating of two molybdenite standards and three molybdenite separates, and was found to be in the range 0.87-1.52% R.S.D. Though accuracy of the method is limited by difficulties in evaluating exact concentration of Os in spike solution, ages obtained in the course of these work agrees well with previously published data.     

Solid-phase synthesis of imidazo[4,5-b]pyridin-2-ones and related urea derivatives by cyclative cleavage of a carbamate linkage

A solid-phase synthesis of substituted cyclic urea derivatives as potential heterocyclic library scaffolds is described. 2-Amino-3-nitropyridine is attached to Wang resin via a carbamate linkage. Reduction of the nitro group was achieved with SnCl(2).2H(2)O. Reductive alkylation with a range of substituted benzaldehydes followed by cyclative cleavage afforded a small library of 3-substituted imidazo[4,5-b]pyridine-2-ones in 33-45% yield and 59-88% purity. Subsequently, this methodology was applied to the synthesis of 3-substituted imidazo[4,5-f]quinolin-2-ones.     

Rational design of an inhibitor of dethiobiotin synthetase; interaction of 6-hydroxypyrimindin-4(3H)-one with the adenine base binding site

Modelling of the H-bonding interactions involved in the binding of the adenine base component of ATP to E. coli dethiobiotin synthetase (DTBS) suggested that 6-hydroxypyrimidin-4(3H)-one (6-HP4) should selectively bind to this site in the enzyme. Kinetic studies show that 6-HP4 is a competitive inhibitor of DTBS and x-ray crystallography shows that 6-HP4 binds specifically in the purine base binding site of the enzyme.     

Mixed Co/Fe oxide nanoparticles in block copolymer micelles

Small iron oxide and Co-doped iron oxide nanoparticles (NPs) were synthesized in a commercial amphiphilic block copolymer, poly(ethylene oxide)-b-poly(methacrylic acid) (PEO 68-b-PMAA8), in aqueous solutions. The structure and composition of the micelles containing guest molecules (metal salts) or NPs (metal oxides) were studied using transmission electron microscopy, dynamic light scattering, X-ray photoelectron spectroscopy, and X-ray powder diffraction. The enlarged micelle cores after incorporation of metal salts are believed to be formed by both PMAA blocks containing metal species and penetrating PEO chains. The nanoparticle size distributions in PEO 68-b-PMAA8 were determined using small-angle X-ray scattering (SAXS) in bulk. Two independent methods for SAXS data interpretation for comprehensive analysis of volume distributions of metal oxide NPs showed presence of both small particles and larger entities containing metal species which are ascribed to organization of block copolymer micelles in bulk. The magnetometry measurements revealed that the NPs are superparamagnetic and their characteristics depend on the method of the NP synthesis. The important advantage of the PEO 68-b-PMAA8 stabilized magnetic nanoparticles described in this paper is their remarkable solubility and stability in water and buffers.     

Use of biosensors for rapid drug residue analysis without sample deconjugation or clean-up: a possible way forward.

The drug salbutamol (SBL) is a beta-agonist that may be used illegally as an animal growth promoter. SBL is also a good example of a drug which is excreted in the form of glucuronides and sulfates. Such metabolites cause complexities in analysing for the presence of drug residues. In the majority of cases a process of deconjugation and sample clean-up is required prior to analysis. This is both time consuming and causes some loss of accuracy. In this study, the urine of calves treated with SBL orally for 3 d was collected during and after medication. Samples were assayed before and after hydrolysis by two different methods, radioimmunoassay (RIA) and a newly developed biosensor immunoassay (BIA). Some samples were also analysed by GC-MS. The results clearly showed that both screening assays (RIA and BIA) found high concentrations of SBL residues throughout the study. This was especially true in the BIA method. It was also demonstrated that urine sample analysis without the need for deconjugation or clean-up could be achieved. Results obtained by GC-MS tended to be an order of magnitude lower than the corresponding screening test results. This work showed that biosensor based veterinary drug residue testing procedures can be developed which can generate results in real time without the need for time consuming sample preparation.     

A new synthesis of pyrrolidines by way of an enantioselective Mannich/diastereoselective hydroamination reaction sequence

A new two-step synthesis of highly substituted pyrrolidines has been developed. Chiral silane Lewis acid promoted enantioselective Mannich reactions of silyl ketene imines with acylhydrazones may be used to access bishomoallylic benzoic hydrazides that in turn may be cyclized to pyrrolidines by way of the thermal hydroamination reaction reported recently by Beauchemin. Importantly, excellent diastereoselectivity may be realized in the hydroamination reactions.