A pharmacophore model for NK2 antagonist comprising compounds from several structurally diverse classes

A neurokinin 2 (NK2) antagonist pharmacophore model has been developed on the basis of five non-peptide antagonists from several structurally diverse classes. To evaluate the pharmacophore model, another 20 antagonists were fitted to the model. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 23 of the 25 antagonists were fitted to the model in a low energy conformation with a low RMS value. The pharmacophore model is described by four pharmacophore elements: Three hydrophobic groups and a hydrogen bond donor represented as a vector. The hydrophobic groups are generally aromatic rings, but this is not a requirement. The antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. The model was able to explain the enantioselectivity of SR48968 and GR159897.     

Sorption and partitioning parameters of benzotriazole compounds

Benzotriazole compounds have major commercial applications as anticorrosive agents in automotive antifreeze and airplane deicer fluids. This study assesses the sorption of benzotriazole (BT), 5-methylbenzotriazole (MBT), and 5-chlorobenzotriazole (CBT) from aqueous solutions to four top soils. The concentration range of 10-500 mg l⁻¹ was used with soils differing in total organic carbon content from 0.27 to 1.72%. Batch systems facilitated the equilibrium sorption with analysis by HPLC. The sorption of these compounds was as much as 60% by mass to a soil with 0.33% Org. C. The log octanol-water partition coefficients (log K_ow) were determined to be 1.23 for BT, 1.89 for MBT, and 2.17 for CBT. The relationship between the log of the sorption partition coefficient, log K_oc and log K_ow differed from previous correlations because hydrophobicity was not the only factor affecting sorption. These compounds have substantial permanent dipole moments as well as being hydrophobic. At high pH where CBT molecules approach their pK_a, sorption was approximately 50% less (by mass) than that of relatively non-ionized CBT molecules.     

Pharmacophore features distributions in different classes of compounds

A pharmacophore analysis approach was used to investigate and compare different classes of compounds relevant to the drug discovery process (specifically, drug molecules, compounds in high throughput screening libraries, combinatorial chemistry building blocks and nondrug molecules). The distributions for a set of pharmacophore features including hydrogen bond acceptors, hydrogen bond donors, negatively ionizable centers, positively ionizable centers and hydrophobic points, were generated and examined. Significant differences were observed between the pharmacophore profiles obtained for the drug molecules and those obtained for the high-throughput screening compounds, which appear to be closely related to the nondrug pharmacophore distribution. It is suggested that the analysis of pharmacophore profiles could be used as an additional tool for the property-based optimization of compound selection and library design processes, thus improving the odds of success in lead discovery projects.     

Performance of (consensus) kNN QSAR for predicting estrogenic activity in a large diverse set of organic compounds

A novel method (in the context of quantitative structure–activity relationship (QSAR)) based on the k nearest neighbour (kNN) principle, has recently been introduced for the derivation of predictive structure–activity relationships. Its performance has been tested for estimating the estrogen binding affinity of a diverse set of 142 organic molecules. Highly predictive models have been obtained. Moreover, it has been demonstrated that consensus-type kNN QSAR models, derived from the arithmetic mean of individual QSAR models were statistically robust and provided more accurate predictions than the great majority of the individual QSAR models. Finally, the consensus QSAR method was tested with 3D QSAR and log?P data from a widely used steroid benchmark data set.     

Performance of (consensus) kNN QSAR for predicting estrogenic activity in a large diverse set of organic compounds

A novel method (in the context of quantitative structure-activity relationship (QSAR)) based on the k nearest neighbour (kNN) principle, has recently been introduced for the derivation of predictive structure-activity relationships. Its performance has been tested for estimating the estrogen binding affinity of a diverse set of 142 organic molecules. Highly predictive models have been obtained. Moreover, it has been demonstrated that consensus-type kNN QSAR models, derived from the arithmetic mean of individual QSAR models were statistically robust and provided more accurate predictions than the great majority of the individual QSAR models. Finally, the consensus QSAR method was tested with 3D QSAR and log P data from a widely used steroid benchmark data set.     

Combinatorial enantiomeric separation of diverse compounds using capillary array electrophoresis

Combinatorial chiral separations were performed on a 96-capillary array electrophoresis system. A comprehensive enantioseparation protocol employing neutral and sulfated cyclodextrins as chiral selectors for common basic, neutral and acidic compounds was developed. By using only four judiciously chosen separation buffers, successful enantioseparations were achieved for 49 out of 54 test compounds spanning a large variety of pK and structures. Therefore, unknown compounds can be screened in this manner to identify the optimal enantioselective conditions in just one run.     

Specific labeling of cell surface proteins with chemically diverse compounds

The specific and covalent labeling of fusion proteins with synthetic molecules opens up new ways to study protein function in the living cell. Here we present a novel method that allows for the specific and exclusive extracellular labeling of proteins on the surfaces of live cells with a large variety of synthetic molecules including fluorophores, protein ligands, or quantum dots. The approach is based on the specific labeling of fusion proteins of acyl carrier protein with synthetic molecules through post-translational modification catalyzed by phosphopantetheine transferase. The specificity and versatility of the labeling should allow it to become an important tool for studying and manipulating cell surface proteins and for complementing existing approaches in cell surface engineering.     

Organozinc compounds of the RZnR′ and ArZnAr′ classes

Conclusions Some unsymmetrical organozinc compounds of the RZnR class (R=phenyl or benzyl, R=2-thienyl) and a number of unsymmetrical aliphatic organozinc compounds were synthesized.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 587–590, March, 1967.     

Extraction of perfluorinated compounds from food matrices using fluorous solvent partitioning

Perfluorinated compounds (PFCs) such as perfluorooctane sulfonic acid (PFOS) have emerged as a new class of global environmental pollutant; they bioaccumulate and are persistent in the environment and in wildlife. Fluorine-fluorine interactions have been investigated as a means to isolate PFCs for mass spectrometric quantification. A novel sample extraction and cleanup procedure has been developed for fat-containing samples based on fluorous liquid-liquid extraction (F-LLE) in a triphasic solvent system consisting of hybrid:fluorous:organic solvent (trifluoroethanol:perfluorohexane/dichloromethane-saturated with water). This system partially separates fluorous from non-fluorous compounds, allowing removal of co-extractants, which had previously resulted in liquid chromatography mass spectrometry (LC-MS/MS) peak suppression preventing low-level detection of PFCs. The developed F-LLE was coupled with an existing extraction protocol allowing the limits of detection of PFCs to be lowered an order of magnitude for high fat samples. The developed workflow was used to show the absence of a range of eleven PFCs in nine UK and one Irish cheese samples. This representative application demonstrates a new application of fluorous-organic extraction in sample cleanup for measurement of fluorinated analytes in food, environment and broader analytical chemistry.     

A convenient route to diverse heterocycles through an addition of beta-amino carbonyl compounds to 3-halogeno-4-methoxybenzynes

[reaction: see text] 3-Halogeno-4-methoxybenzynes 5 generated from 5-(3-halogeno-4-methoxyphenyl)thianthrenium perchlorates 1 and LDA in THF at reflux reacted with various beta-amino carbonyl compounds and 2-aminophenyl benzenesulfonate etc. to give diverse heterocyclic compounds.     

Biotransformations of drugs belonging to nitrogen heterocycles

The present review covers general aspects related to the metabolism of organic compounds, primarily, of biologically active azaheterocycles used as drugs. Compounds of this type occupy a dominant place among known drugs. Data on the main chemical processes determining the pathways of principal biotransformations, such as redox reactions, hydrolysis, alkylation, acylation, various conjugations, isomerizations, and condensations, are summarized. The metabolisms of heterocycles is considered based on the ring size of the substrate.     

Synthesis of thiosulfonates belonging to quinoline derivatives

S-Esters of 8-quinolinethiosulfonic acid were synthesized and tested for antimicrobial activity.