Chiral 1,4-benzodiazepines. XII. Conformation in a solution of 7-chloro-5-phenyl-3(S)methyl-1,3-dihydro-2H-1,4-benzodiazepine

Deuterium labeled congeners of 7-chloro-5-phenyl-3(S)-methyl-1,3-dihydro-2H-1,4-benzodiazepine ( 8 ), i.e., compounds 9 and 16-18 were prepared and their lis-nmr spectra run. For computational studies compounds 9 and 16 were chosen. The results of lis measurements revealed that 16 is present in more than 97% in the boat-like conformation I (Scheme 3).     

Chiral 1,4-benzodiazepines—-XI: Kinetics of degenerate nucleophilic exchange of C(3)-hydroxy group

The rate for degenerate nucleophilic exchange (k_e) of the C(3)-OH group in the racemic compound 1 was determined in DMSO/H₂¹⁸O using mass spectrometry. Epimerization rates for diastereomers 15 and 16 were determined by polarimetry (k_ep) and NMR spectroscopy (k_r-c—for $\text{r}$ing-$\text{c}$hain tautomery). The ratio $\text{k}{}_{\mathrm{e}}\text{k}{}_{\mathrm{ep}}$ ~ 3.5 35° is close to that obtained for degenerate nucleophilic exchange of the C(3)-OMe group in the compound 1a ($\text{k}{}_{\mathrm{e}}\text{k}{}_{\mathrm{\alpha }}$ ~4, Refs. [3,4]). These data confirm the C(3)-OH substituted 1,4-benzodiazepin-2-ones lose the configurational identity of the C(3) chiral centre by both direct nucleophilic substitution of the OH group, and ring-chain tautomery processes.The synthesis of the diastereomeric compounds 15 and 16, and their chromatographic separation is described.     

Free volume properties of a linear soft polymer: a computer simulation study

Molecular dynamics simulation of a linear soft polymer has been performed and the free volume properties of the system have been analyzed in detail in terms of the Voronoi polyhedra of the monomers. It is found that there are only small density fluctuations present in the system. The local environment of the monomers is found to be rather spherical, even in comparison with liquids of atoms or small molecules. The monomers are found to be, on average, eight coordinated by their nearest geometric neighbors, including intra-chain and inter-chain ones. The packing of the monomers is found to be rather compact, in a configuration of 1900 monomers there are, on average, only three voids large enough to incorporate a spherical particle as large as a monomer, indicating that the density of the large vacancies in the system is considerably, i.e., by a few orders of magnitude lower than in molecular liquids corresponding to roughly the same reduced densities.     

Syntheses of polysubstituted pyrroles and of 2,3-disubstituted quinoxalines and substituted benzo[g]quinoxalines

Tetraacetylethylene ( 1 ), and cis-diacetylethylene ( 4 ) reacted under mild conditions with 3-amino-2-butenoic acid methyl ester ( 6 ), benzene-1,2-diamine and naphthalene-2,3-diamine to give polysubstituted pyrroles, 2,3-disubstituted quinoxalines and 2,3-disubstituted benzo[g]quinoxalines respectively. Some aspects of the reactions mechanisms are discussed.     

Magnetic response of nonmagnetic impurities in cuprates

A theory of the local magnetic response of a nonmagnetic impurity in a doped antiferromagnet, as relevant to the normal-state in cuprates, is presented. It is based on the assumption of the overdamped collective mode in the bulk system and on the evidence that equal-time spin correlations are only weakly renormalized in the vicinity of the impurity. The theory relates the Kondo-like behavior of the local susceptibility to the anomalous temperature dependence of the bulk magnetic susceptibility.     

Dominant pathways in protein folding

We present a method to investigate the kinetics of protein folding and the dynamics underlying the formation of secondary and tertiary structures during the entire reaction. By writing the solution of the Fokker-Planck equation in terms of a path integral, we derive a Hamilton-Jacobi variational principle from which we are able to compute the most probable pathway of folding. The method is applied to the folding of the Villin headpiece subdomain simulated using a Go model. An initial collapsing phase driven by the initial configuration is followed by a rearrangement phase, in which secondary structures are formed and all computed paths display strong similarities. This completely general method does not require the prior knowledge of any reaction coordinate and is an efficient tool to perform simulations of the entire folding process with available computers.     

Counterion binding in the aqueous solutions of bile acid salts, as studied by computer simulation methods

We investigate the structural and dynamical properties of counterion binding in sodium cholate and sodium deoxycholate micelles at three different concentration, namely, 30, 90, and 300 mM, by means of molecular dynamics simulations at the atomistic level. The obtained results can resolve a long-standing, apparent contradiction between different experiments that reported discordant values for the degree of counterion binding. Namely, our results suggest that certain experimental techniques, such as freezing point depression, are only sensitive to the contact counterions, and hence, the degree of contact binding of the counterions is measured. On the other hand, in experiments employing, e.g., electrode potential or nuclear magnetic resonance measurements, the solvent-separated counterions also contribute to the signal detected, and hence, the counterions that are measured as bound ones do include the solvent-separated counterions as well.     

Uncertainty evaluation for the quantification of low masses of benzo[a]pyrene: Comparison between the Law of Propagation of Uncertainty and the Monte Carlo method

A proper evaluation of the uncertainty associated to the quantification of micropollutants in the environment, like Polycyclic Aromatic Hydrocarbons (PAHs), is crucial for the reliability of the measurement results. The present work describes a comparison between the uncertainty evaluation carried out according to the GUM uncertainty framework and the Monte Carlo (MC) method. This comparison was carried out starting from real data sets obtained from the quantification of benzo[a]pyrene (BaP), spiked on filters commonly used for airborne particulate matter sampling. BaP was chosen as target analyte as it is listed in the current European legislation as marker of the carcinogenic risk for the whole class of PAHs.     

A toxicity evaluation and predictive system based on neural networks and wavelets

A computational approach has been developed for performing efficient and reasonably accurate toxicity evaluation and prediction. The approach is based on computational neural networks linked to modern computational chemistry and wavelet methods. In this paper, we present details of this approach and results demonstrating its accuracy and flexibility for predicting diverse biological endpoints including metabolic processes, mode of action, and hepato- and neurotoxicity. The approach also can be used for automatic processing of microarray data to predict modes of action.