Elastomers: Sulphur or peroxide cross-linked? An analytical approach

The analytical methods presented in this study lead to a characterisation of the vulcanisation system of unknown elastomers. The chemical determination of sulphur gives a first impression of the system. However, it cannot be proved with any degree of certainty weather a product is sulphur cross-linked or not. Other wet chemical methods (colour reactions) are more suitable for quality control of already known systems. Most spectrometric methods (infrared spectrometry, Raman spectrometry, nuclear resonance spectrometry) are only of use for special applications and for research. A more precise characterisation is obtained by means of chromatographic methods, i.e. by identifying the products, which originated from thermal degradation of the cross-linking reagents (sulphur, sulphur donators, peroxides. Evolved-Gas-Analysis (EGA) and pyrolysis gas chromatography with adequate detectors proved to be very successful as chemical-analytical methods for such investigations. In order to make a reliable statement about the vulcanisation system of unknown elastomeric material, the results of several analytical methods have to be collected and evaluated.Conference Pape

Development of a Pharmacophore for Inhibition of Human Liver Cytochrome P-450 2D6: Molecular Modeling and Inhibition Studies.

To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1′-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 μM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 Å from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 Å and 6.6-7.5 Å from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted

Quinolone antibacterial agents: Relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2.

The inhibitory effect of 44 quinolone antibacterials and derivatives (common structure, 4-oxoquinoline-3-carboxylic acid) on cytochrome P450 isoform CYP1A2 activity was tested using human liver microsomes and caffeine 3-demethylation as a specific test system for this enzyme. By direct comparison of molecules differing structurally in only one position, the following structure-activity relationships were found. 3′-Oxo derivatives had a reduced or similar activity and M1 metabolites (cleavage of piperazinyl substituent) had a greater inhibitory activity, compared with the parent molecule. Alkylation of the 7-piperazinyl substituent resulted in a reduced inhibitory potency. Naphthyridines with an unsubstituted piperazinyl group at position 7 displayed a greater inhibitory potency than did corresponding quinoline derivatives. Derivatives with a fluorine substitution at position 8 had only a minor effect. Molecular modeling studies with inhibitors and caffeine showed that it is possible to explain the potency of the quinolones to inhibit CYP1A2 on a molecular level. The keto group, the carboxylate group, and the core nitrogen at position 1 are likely to be the most important groups for binding to the active site of CYP1A2, because the molecular electrostatic potential of all inhibitors is very similar to that of caffeine in these regions. The presence of a piperazinyl substituent, however, seems to be no prerequisite for inhibitory potency. Finally, an equation to estimate the potency to inhibit CYP1A2 was developed by quantitative structure-activity relationsip analysis