A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites

Summary A representative range of pyrimidine nucleoside analogues that are known to inhibit herpes simplex virus (HSV) replication have been used to construct receptor binding site models for the varicella-zoster virus (VZV), thymidine kinase (TK) and human TK1. Given a set of interacting ligands, superimposed in such a manner as to define a pharmacophore, the pseudoreceptor modelling technique Yak provides a means of building binding site models of macromolecules for which no three-dimensional experimental structures are available. Once the models have been evaluated by their ability to reproduce experimental binding data [Vedani et al., J. Am. Chem. Soc., 117 (1995) 4987], they can be used for predictive purposes. Calculated and experimental values of relative binding affinity are compared. Our models suggest that the substitution of one residue may be sufficient to determine ligand subtype affinity.     

Erprobte Verfahren zur Ultramikro-Elementaranalyse

Zusammenfassung Es wird über ein allgemein anwendbares Verfahren zur CH-Bestimmung mit Einwaagen von 0,4–1 mg berichtet. Die Verbrennung erfolgt in einer verkleinerten Pregl-Apparatur, wobei als Verbrennungs- und Treibgas Helium mit 5–10% Sauerstoff dient. Wasser und Kohlendioxid werden aus dem Gasstrom ausgefroren, in einer evakuierten zweiteiligen Meßapparatur fraktioniert umkondensiert und dort über ihre Drucke bestimmt.

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Summary A generally applicable method is described for the determination of carbon and hydrogen with sample weights of 0.4 to 1 mg. The combustion is carried out in a very small, modified Pregl-apparatus, employing helium containing 5–10% oxygen as combustion and entraining gas. Water and carbon dioxide are removed from the gas stream by freezing. Then water and carbon dioxide are evaporated and fractional-condensed in a vacuum apparatus, where their quantities are determined by their pressures.

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Die Versuche wurden außerordentlich sorgfältig von Herrn Nicklas durchgeführt.     

The crystal and molecular structure of the cycloadduct from an activated carbodiimide and methyl isothiocyanate

The crystal and molecular structures of the cycloadduct from isopropyl[α-(dimethylthio-carbamoyl)isopropyl]carbodiimide and methyl isothiocyanate were determined by single-crystal X-ray methods. The product was established to be 2-(1-isopropyl-3,5-dimethyl-4,6-dithioxo-hexahydro-1,3,5-triazine-2-ylidenamino)-N,N-dimethylthioisoburyramide, in which contrary to expectations based on hybridisation the heterocyclic ring adopts a boat conformation.     

Alkylsulfamoyl Chlorides as Key Units in the Synthesis of Novel Biologically Active Compounds for Crop Protection

Due to their bifunctional character, alkylsulfamoyl chlorides are versatile units for the synthesis of heterocycles, polar sulfamates, and sulfonamides. In the last decade, synthetic methods of general preparative use have been developed, by means of which amine hydrochlorides, isocyanates, aziridines or tertiary alcohols can be reacted with suitable sulfuric acid derivatives to give novel, variously substituted alkylsulfamoyl chlorides. These compounds can subsequently be converted either to previously unobtainable N-alkoxyalkyl-N-alkylsulfamoyl chlorides or to novel heterocycles of the type 1H-2,1,3-benzothiadiazin-4-one-2,2-dioxide, 2H-1,2,6-thiadia-zin-3-one-1,1-dioxide and 2H-1,2,4,6-thiatriazin-5-one-1,1-dioxide; these compounds are examples of interesting models which illustrate the relation between the structure and the action of the compound, and in some cases lead to highly selective, ecologically unobjectionable herbicides. On the other hand, the alkylsulfamoyl chlorides themselves can be N-acylated to give further 3- to 5-atom bifunctional synthesis units, with which novel heterocyclic syntheses can be carried out. Further uses of the alkylsulfamoyl chlorides include the preparation of biologically active sulfamates, and cycloaddition reactions of N-sulfonylamines prepared in situ.     

Molecular dynamics simulations of the dinuclear zinc-beta-lactamase from Bacteroides fragilis complexed with imipenem

Herein, we present results from MD simulations of the Michaelis complex formed between the dizinc beta-lactamase from B. fragilis and imipenem. We considered two catalytically important configurations, which differ in the presence or absence of a hydroxide bridge connecting the two zinc ions in the active site. The structural and dynamical effects induced by substrate binding, the specific roles of the conserved residues and the zinc-bound water molecules, the near attack conformers of the Michaelis complex, and so forth, are discussed in detail. The relative stability of the two configurations was estimated from QM linear scaling calculations on the enzyme-substrate complex combined with Poisson-Boltzmann electrostatic calculations and normal mode calculations. Importantly, we find that the two configurations have similar energies, indicating that these two structures could readily be interchanged, thereby facilitating catalysis. The configuration with the hydroxide bound to the two zinc ions is predicted to be the resting form of the enzyme, while the configuration without the bridge is the reactive form that was found to place the hydroxide in position to attack the carbonyl of the beta-lactam ring. Thus, we propose that the enzyme initiates catalysis by converting from the hydroxide bridge form into the configuration that lacks the hydroxide bridge. This interconversion increases the nucleophilicity of the hydroxide ion and exposes it to the beta-lactam carbonyl, which ultimately facilitates nucleophilic attack. The implications of the observed modes of binding, the possible influence of mutating the Lys184 and Asn193 residues on substrate binding, and the reaction mechanism are also discussed in detail.     

Aza-Claisen Rearrangement: Synthesis of 5′-branched 5′-aminothymidines

The syntheses of both diastereoisomers of 5′-ethyl-substituted thymidine dimers, the (5′R)- and (5′S)-configurated 33a and 33b respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3′)-CH₂CONH-CH(5′)(Et)), arc described. Their fully protected derivatives 35a and 35b , respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted Pd^II-catalysed aza-Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17 , whose structure was confirmed by X-ray analysis.     

Heterocyclen aus α-nitroolefinen. XI . 1,2-oxazine aus α-nitroolefinen und β-dicarbonylverbindungen

Dihydro-1,2-oxazines 8 and 12-oxazines 12 are formed by the reaction of the nitronic acids of the adducts of α-nitroolefins and β-dicarbonyl compounds ( 6 ) by two ways: A ) The nitronic acids 6 are heated in a boiling solution of urea in ethanol or methanol. B ) The nitronic acids 6 are reduced with an aqueous solution of ammoniachloride and sodium sulfide. ¹H-nmr and ¹³C-nmr investigations prove the constitutions. The mechanism is discussed.     

Simultane Bestimmung von elektrophoretischer Beweglichkeit und Teilchengröße bei überlagerter Konvektion an Suspensionen und Emulsionen

With AWPS (Amplitude Weighted Phase Structuration), a new signal processing scheme is demonstrated for the simultaneous determination of zeta potentials and particle sizes. It allows the measurements of a small electrophoretic mobility in the presence of large particle diffusion and constant velocity, e. g. due to thermal convection. Laser light scattering techniques instead of the former methods determine electrophoretic velocity more objectively and precisely. The applicability of laser measurement techniques by analysis of the frequency spectrum is limited for particles ?50 nm or very low potentials, because of the broadening of the spectral peak by Brownian motion. In contrast to AWPS a separation of the various kinds of collective motion is not possible. The presented results demonstrate that this separation is of considerable significance in the acquisition of reliable values. Additionally the novel signal processing scheme allows a significant increase in sensitivity and therefore the application of an oscillating field (50–100 Hz) with a very small field strength. The system is feasible for particle sizes in the range of a few nm up to several μm. Its high resolution allows experiments with low fields or with small zeta potentials, even in the critical particles size range of a few nanometers.