Antiviral drug Triazavirin,selectively labeled with 2H, 13C,and 15N stable isotopes. Synthesis and properties

Chemistry of Heterocyclic Compounds - Isotope-labeled antiviral drug Triazavirin containing 2H, 13C, and 15N atoms in its structure has been synthesized. 13C2H3I and KS13CN served as donors of 13C...     

Development of the force field parameters for phosphoimidazole and phosphohistidine

Phosphorylation of histidine-containing proteins is a key step in the mechanism of many phosphate transfer enzymes (kinases, phosphatases) and is the first stage in a wide variety of signal transduction cascades in bacteria, yeast, higher plants, and mammals. Studies of structural and dynamical aspects of such enzymes in the phosphorylated intermediate states are important for understanding the intimate molecular mechanisms of their functioning. Such information may be obtained via molecular dynamics and/or docking simulations, but in this case appropriate force field parameters for phosphohistidine should be explicitly defined. In the present article we describe development of the GROMOS96 force field parameters for phosphoimidazole molecule--a realistic model of the phosphohistidine side chain. The parameterization is based on the results of ab initio quantum chemical calculations with subsequent refinement and testing using molecular mechanics and molecular dynamics simulations. The set of force constants and equilibrium geometry is employed to derive force field for the phosphohistidine moiety. Resulting parameters and topology are incorporated into the molecular modeling package GROMACS and used in molecular dynamics simulations of a phosphohistidine-containing protein in explicit solvent.     

Determination of Testosterone Metabolites in Rat Hepatocytes with and without Cryopreservation by On-Line SPE Column-Switching LC and MS Detection

In a recently published paper development of a sensitive automated “on-line” solid-phase extraction (SPE)/RP-HPLC assay for 6β-hydroxytestosterone (6β-OHT) with corticosterone as the internal standard (IS) was reported and its potential for quantification of various testosterone metabolites in culture media reflecting metabolic activity of cultured human and animal hepatocytes demonstrated [1]. In this following contribution the technique has been extended to determination of another five testosterone metabolites in cultured rat hepatocytes using an identical “on-line” SPE/RP-HPLC procedure and detection by tandem MS-MS with an atmospheric pressure chemical ionization (APCI) source in the selected reaction monitoring (SRM) mode as that described in [1]. All six testosterone metabolites, namely 2α-OHT, 2β-OHT, 6α-OHT, 6β-OHT, 7α-OHT and 16α-OHT, could be sufficiently separated from each other and thus an unequivocal assignment to the individual structures was achieved. Validation data are presented specifying the limits of quantitation as well as the mean values of the coefficients of variation (CV) for the target analytes and the accuracy obtained at five different days. Regio- and stereoselective testosterone hydroxylation by rat hepatocytes was measured in a long-term culture system with and without exposure to rifampicin as an inducer of liver CYP 3A4 activity. In addition, testosterone hydroxylation was analyzed in cultures of cryopreserved hepatocytes that had been stored at −196 °C. The rat hepatocytes were cultured after thawing for up to 11 days and induction of testosterone hydroxylase activity could be demonstrated in cultures which underwent a new cryopreservation protocol. This paper is dedicated to Professor Hinrich Cramer on the occasion of his 75th birthday.     

Implicit two-phase solvation model as a tool to assess conformation and energetics of proteins in membrane-mimetic media

 A heterogeneous implicit membrane-mimetic model is applied to simulations of membrane proteins. The model employs atomic solvation parameters for gas–water and gas–cyclohexane transfer. It is used to analyze structure, energetics, and orientation with respect to the bilayer of two polypeptides with different modes of membrane binding – hydrophobic segment of human glycophorin A (GpA) and cytotoxin II from Naja naja oxiana snake venom (CTX). The native state of GpA represents a transmembrane (TM) α helix, while CTX is a water-soluble protein, which is able to interact with the cell membrane. The conformational space of the polypeptides was explored in Monte Carlo simulations. The results show that the most stable conformers of GpA represent a TM α helix. They are additionally stabilized by an applied TM voltage. The results also show that CTX inserts with its three loops, does not cross the hydrophobic layer, and stays partially immersed in the membrane. This agrees well with the experimental data, thus confirming the validity of the solvation model. Received: 13 June 2000 / Accepted: 15 September 2000 / Published online: 19 January 2001     

Evaluation of cross-peak volumes in 2D-spectra using 1D-fitting of line shapes

An interactive technique for the evaluation of cross-peak volumes in 2D-spectra is presented, based on a 1D nonlinear curve-fitting procedure. The effects of applied window functions, truncation of time domain data and cross-peak overlap on the evaluated cross-peak volumes are considered. The technique is applied to crowded NOESY spectra of the 34–65 and 163–231 fragments of bacterioopsin ofHalobacterium halobium. For these spectra 284 and 546 cross-peak volumes were measured with high accuracy.     

Reactions of trimethinecyanines of the 1,3-dioxenium series with nucleophiles. The structures of the parent carbocation and of a product of its reaction with methanol

The chemistry and the regioselectivity of alcoholysis, aminolysis, and hydrolysis of symmetrical trimethinecyanine carbenium ions in 4-[3-(2,2-diorganyl-6-phenyl-4H-1,3-dioxen-4-ylidene) prop-1-enyl]-2,2-diorganyl-6-phenyl-1,3-dioxenium perchlorates (4a,b) were investigated. The structures of trimethinecyanine 4,5:4′,5′-bisannelated at the methine chain (3) and of a product of the reaction of nonannelated trimethinecyanine with the methoxide anion were established by X-ray diffraction analysis,¹H NMR spectroscopy, and quantum-chemical calculations (PM3). The nucleophile attacks the mesomeric π-conjugated system of the trimethinecyanine cation selectivily at the C(6) atom of one of the dioxenium fragrments, the second dioxenium ring being deactivated. Alcoholysis affords products of addition of the methoxy group to trimethinecyamines. In the course of aminolysis and hydrolysis, the dioxenium ring that is subjected to the attack eliminates acetone to form 1,3-dioxenylidenepropenylic derivatives of 1,3-enaminoketones and 1,3-ketoenols, respectively. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 521–529, March. 1999.     

Resonances and tunneling in a quantum wire

We consider a problem in mathematical scattering theory related to the ballistic conductance model. The model under investigation describes the charge propagation in a quantum wire. We assume that the charge carrier has a spin and take the Rashba spin-orbital interaction into account. We study the conductance resonances generated by the weak quantum-wire interaction with the quasistationary state of a parallel-connected quantum dot or with the tunneling through a series-connected quantum dot. Such a quantum dot is usually the control element. We present sufficient conditions for the spatial symmetry of the system to ensure that the quasistationary state of the quantum dot generates a conductance resonance. We assume that the conductance is related to the scattering matrix by the Landauer formula. __________ Translated from Teoreticheskaya i Matematicheskaya Fizika, Vol. 147, No. 1, pp. 92–102, April, 2006.     

Electromagnetic fields in tornados and spouts

The electrical and magnetic fields in tornados and spouts were calculated on the basis of theoretical data. The calculation results were compared to the data from observations.     

Model-Free Approach beyond the Borders of Its Applicability

Model calculations presented in this article show that commonly used methodology of¹⁵N relaxation data analysis completely fails in detecting nanosecond time scale motions if the major part of the molecule is involved in these motions. New criteria are introduced for the detection of such cases, based on the dependence of the apparent overall correlation time, derived from theT₁/T₂ratio, on the spectrometer frequency. Correctly estimating the overall rotation correlation time τ_Rwas shown to play the key role in model-free data analysis. It is found, however, that in cases of slow internal motions with characteristic times of more than 3–4 ns, the effective τ_Rprovided by theT₁/T₂ratio for individual amide nitrogens can be used for the characterization of the fast picosecond internal dynamics.