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Höflichkeit ist ein wichtiges Thema laienlinguistischer Überlegungen zu Sprache und Kommunikation. Seit einiger Zeit hat es sich auch zu einem zentralen Gegenstand linguistischer Forschungsansätze entwickelt. Der Band stellt die wichtigsten sprachwissenschaftlichen Theorien zur Höflichkeit vor und zeigt ihre Verflechtung mit Nachbardisziplinen auf. Es handelt sich um die erste deutschsprachige Publikation, die einen aktuellen Überblick über das Forschungsgebiet samt Anwendungsfeldern bietet.

Proline-based trypsin inhibitors occupying the S1–S2–S1′ region were identified by an HTS screening campaign. It was discovered that truncation of the P1′ moiety and appropriate extension into the S4 region led to highly potent trypsin inhibitors with excellent selectivity against related serine proteases and a favorable hERG profile.

Recently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g., 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2.

A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.

The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the nonprime and S1' pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3(sp) cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

The new hexathiodiphosphate(IV) hydrates K4[P2S6] · 4 H2O (1), Rb4[P2S6] · 6 H2O (2), and Cs4[P2S6] · 6 H2O (3) were synthesized by soft chemistry reactions from aqueous solutions of Na4[P2S6] · 6 H2O and the corresponding heavy alkali-metal hydroxides. Their crystal structures were determined by single crystal X-ray diffraction. K4[P2S6] · 4 H2O (1) crystallizes in the monoclinic space group P 21/n with a = 803.7(1), b = 1129.2(1), c = 896.6(1) pm, β = 94.09(1)°, Z = 2. Rb4[P2S6] · 6 H2O (2) crystallizes in the monoclinic space group P 21/c with a = 909.4(2), b = 1276.6(2), c = 914.9(2) pm, β = 114.34(2)°, Z = 2. Cs4[P2S6] · 6 H2O (3) crystallizes in the triclinic space group with a = 742.9(2), b = 929.8(2), c = 936.8(2) pm, α = 95.65(2), β = 112.87(2), γ = 112.77(2)°, Z = 1. The structures are built up by discrete [P2S6]4− anions in staggered conformation, the corresponding alkali-metal cations and water molecules. O ··· S and O ··· O hydrogen bonds between the [P2S6]4− anions and the water molecules consolidate the structures into a three-dimensional network. The different water-content compositions result by the corresponding alkali-metal coordination polyhedra and by the prefered number of water molecules in their coordination sphere, respectively. The FT-Raman and FT-IR/FIR spectra of the title compounds have been recorded and interpreted, especially with respect to the [P2S6]4− group. The thermogravimetric analysis showed that K4[P2S6] · 4 H2O converted to K4[P2S6] as it was heated at 100 °C.

The thermal decomposition of Ni(NO3)2·6H2O (1), Ca(NO3)2·4H2O (2) and nitryl/nitrosyl nitrato nickelate(II), NO2/NO[Ni(NO3)3] (3), was investigated by thermogravimetric measurements with quasi-isothermal conditions and compared to Co(NO3)2·6H2O. The respective decomposition processes of 1 and 2 differ from each other showing that at one hand anhydrous Ca(NO3)2 was obtained whereas anhydrous nickel dinitrate has not be formed due to redox and condensation reactions. Instead basic nickel compounds have been formed. In reducing atmosphere nickel metal can be obtained. Anhydrous Ni(NO3)2 results by the thermal degradation of nitryl/nitrosyl nitrato nickelate. FT-Raman spectra have been of help in the judgement of the decomposition processes.

Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing.

Single crystals of rubidium hexathiodiphosphate(V), Rb2P2S6, have been obtained and investigated by single crystal X-ray diffraction, and IR/FIR and Raman spectroscopy. The title compound crystallizes isotypically to the potassium, caesium and thallium analogues in the orthorhombic space group Immm (no. 71) with a = 8.485(3), b= 6.953(3), c =9.259(3 Å , and Z = 2, final R1= 0.0579 and wR2 = 0.0987. The crystal structure is characterized by discrete [P2S6]2− anions (edge-sharing double-tetrahedra) with D2h symmetry. Rubidium is coordinated by ten sulfur atoms forming a slightly distorted two-capped tetragonal prism with a coordination number CNRb 10. The FT-Raman and FT-IR/FIR spectra have been recorded and a factor group analysis was carried out.

Polyvalent carbohydrate-protein interactions occur frequently in biology, particularly in recognition events on cellular membranes. Collectively, they can be much stronger than corresponding monovalent interactions, rendering it difficult to control them with individual small molecules. Artificial macromolecules have been used as polyvalent ligands to inhibit polyvalent processes; however, both reproducible synthesis and appropriate characterization of such complex entities is demanding. Herein, we present an alternative concept avoiding conventional macromolecules. Small glycodendrimers which fulfill single molecule entity criteria self-assemble to form non-covalent nanoparticles. These particles-not the individual molecules-function as polyvalent ligands, efficiently inhibiting polyvalent processes both in vitro and in vivo. The synthesis and characterization of these glycodendrimers is described in detail. Furthermore, we report on the characterization of the non-covalent nanoparticles formed and on their biological evaluation.

The thermal decomposition of Co(NO3)2·6H2O (1) as well as that one of NO[Co(NO3)3] (Co(NO3)2·N2O4) (2) was followed by thermogravimetric (TG) measurements, X-ray recording and Raman and IR spectra. The stepwise decomposition reactions of 1 and 2 leading to anhydrous cobalt(II)nitrate (3) were established. In N2 atmosphere, cobalt oxides are finally formed whereas in H2/N2 (10% H2) cobalt metal is produced. Rapid heating of cobalt(II)nitrate hexahydrate causes melting (formation of a hydrate melt) and therefore side reactions in the hydrate melt by incoupled reactions and evolution/evaporation of different species as, e.g., HNO3, NO2, etc. In case of larger amounts in dense packing in the sample container, the formation of oxo(hydoxo)nitrates is possible at higher temperature. For 2, its thermal decomposition to 3 was followed and its decomposition mechanism is proposed.

1,4-Diazepane-2,5-diones (2) are found to be a new class of potent LFA-1 inhibitors. The synthesis, structure, and biological evaluation of these 1,4-diazepine-2,5-diones and related derivatives are described.

Based on the structural comparison of the S1 pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesized as inhibitors of thrombin. Among the novel compounds, a number of derivatives were synthesized which appeared to have side-chain variants too big to fit into the S1 pocket. Nevertheless, these compounds inhibited thrombin in the nM range. The X-ray structure of one of these inhibitors bound to the active side of thrombin reveals that a new binding mode is responsible for these surprising results.

We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused bicyclic core structure that fills the S2 pocket of the active site of thrombin. The bicycle introduces conformational constraint into the ligand and locks the Xaa-Pro amide bond into the desired trans configuration. Among the known ring systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as our basic template. The influence of several structural features was analyzed: the length of the argininal side chain, the stereochemistry at C6, and the importance of making optimal use of the S3 pocket. Finally, an X-ray crystal structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3 A. These designed thrombin inhibitors, which were prepared by an efficient synthesis, showed high selectivity over trypsin and other serine proteases. Further derivation based on the information obtained by X-ray crystallography should certainly allow to improve the potency.

Computer-aided ligand design is an active, challenging, and multidisciplinary research field that blends knowledge of biochemistry, physics, and computer sciences. Whenever it is possible to experimentally determine or to model the three-dimensional structure of a pharmacologically relevant enzyme or receptor, computational approaches can be used to design specific high-affinity ligands. This article describes methods, applications, and perspectives of computer-assisted ligand design.

Graphite intercalation compounds (GICs) with the trichlorides of Y, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu have been prepared and characterized by chemical analysis and X-ray diffraction. Attempts to synthesize binary GICs with LaCl3, CeCl3, PrCl3, and NdCl3 failed. By heating mixtures of YCl3 + LnCl3 (Ln = La - Lu) with graphite ternary GICs were obtained. The molar ratios LnCl3:YCl3 in the GICs were found to increase from La to Dy which runs parallel to the decrease in the ionic radii of the Ln3+ ions.

The uptake of ammonia by copper chloride graphite intercalation compounds was studied. The products obtained can be represented by the formula {xC}CuCl2·nNH3. They are regarded to be occlusion complexes. The thermal decomposition of these complexes has been studied and compared with those of ammine complexes of CuCl2. The techniques used were thermogravimetric analysis supported by chemical analysis and X-ray diffraction. When heated in a slow stream of ammonia or nitrogen, ammonia is lost in steps, which are better defined when the decomposition takes place in ammonia. The decomposition finally leads to the formation of CuCl mixed with graphite.

Thrombin is a multifunctional protein: in addition to its role in coagulation, thrombin has important biological effects on platelets, endothelial and smooth muscle cells, leukocytes, the heart and neurones. A detailed understanding of the structure of thrombin, of related serine proteases and of enzyme-inhibitor complexes has aided in the discovery of potent and selective new inhibitor molecules. Some of these novel thrombin inhibitors are active when administered orally and have shown remarkable efficacy as antithrombotic agents in animal models, offering a greater therapeutic potential than presently available drugs. This potential extends also to non-thrombotic indications where thrombin may be involved, namely inflammation, cancer and neurodegenerative diseases. The recent identification of specific thrombin receptors on different cells provides an alternative strategy for inhibiting thrombin's cellular actions, without necessarily compromising its role in haemostasis. In this review, Carlo Tapparelli and colleagues present a comprehensive update of these recent developments in the field of thrombin biology and pharmacology suggesting a new era of therapeutic drugs is on the horizon.

Single crystals of the title compound, CaNa(2)(P(2)S(6))·8H(2)O, were obtained by adding calcium hydroxide to an aqueous solution of Na(4)(P(2)S(6))·6H(2)O. The structure is isotypic with that of its strontium analogue and consists of one Ca(2+) cation, two Na(+) cations, one-half of a centrosymmetric (P(2)S(6))(4-) anion with staggered confirmation and four water mol-ecules in the asymmetric unit. The crystal structure can be described as being built up from layers of cations and anions extending parallel to (101). Within a layer, each CaO(8) polyhedron is connected via edge-sharing to two NaO(4)S(2) octa-hedra and to one NaO(2)S(4) octa-edron. The NaO(4)S(2) octa-hedra are, in turn, linked with two (P(2)S(6))(4-) anions through common corners. Various O-H⋯S hydrogen-bonding inter-actions lead to cohesion of adjacent layers. The Ca(2+) and one Na(+) cation are situated on a twofold rotation axis and the second Na(+) cation is situated on an inversion centre.

Dem Thema 'Sprachliche Hoflichkeit' wird wieder eine verstarkte Aufmerksamkeit in Linguistik und Didaktik zuteil. Im Kontext zunehmender Internationalisierung und dem damit verbundenen hoheren Aufkommen an interkultureller Kommunikation, aber auch im Kontext der zunehmenden Verbreitung neuer Medien ergeben sich neue Fragestellungen fur Theoriebildung und Methodenentwicklung. Der Sammelband prasentiert 17 Beitrage zu theoretischen und methodischen Grundlagen, zu kulturkontrastiven und interkulturellen Themenstellungen sowie Vorschlage zum DaF-Unterricht. Neben historischen und aktuellen Beschreibungsansatzen werden Realisationsformen sprachlicher Hoflichkeit am Beispiel von verschiedenen Sprachhandlungsmustern und Textsorten sowie Kommunikationsdomanen in unterschiedlichen kulturellen Kontexten analysiert. Schliesslich folgt ein Ausblick auf interkulturelle Trainings und DaF-Lehrwerke."

A series of novel maleimide-based inhibitors of protein kinase C (PKC) were designed, synthesized, and evaluated. AEB071 (1) was found to be a potent, selective inhibitor of classical and novel PKC isotypes. 1 is a highly efficient immunomodulator, acting via inhibition of early T cell activation. The binding mode of maleimides to PKCs, proposed by molecular modeling, was confirmed by X-ray analysis of 1 bound in the active site of PKCalpha.

Single crystals of rubidium hexathiodiphosphate(V), Rb 2 P 2 S 6 , have been obtained and investigated by single crystal X-ray diffraction, and IR/FIR and Raman spectroscopy. The title compound crystallizes isotypically to the potassium, caesium and thallium analogues in the orthorhombic space group Immm (no. 71) with a = 8.485(3), b = 6.953(3), c = 9.259(3) A, and Z = 2, final R1 = 0.0579 and wR2 = 0.0987. The crystal structure is characterized by discrete [P 2 S 6 ] 2- anions (edge-sharing double-tetrahedra) with D 2h symmetry. Rubidium is coordinated by ten sulfur atoms forming a slightly distorted two-capped tetragonal prism with a coordination number CN Rb 10. The FT-Raman and FT-IR/FIR spectra have been recorded and a factor group analysis was carried out.

With the aim of discovering potent and selective dengue NS3 protease inhibitors, we systematically synthesized and evaluated a series of tetrapeptide aldehydes based on lead aldehyde 1 (Bz-Nle-Lys-Arg-Arg-H, K(i)=5.8 microM). In general, we observe that interactions of P(2) side chain are more important than P(1) followed by P(3) and P(4). Tripeptide and dipeptide aldehyde inhibitors also show low micromolar activity. Additionally, an effective non-basic, uncharged replacement of P(1) Arg is identified.

The constants of binding of five peptide analogs to the active site of the HIV-1 aspartic-protease are calculated based on a novel sampling scheme that is efficient and does not introduce any approximations in addition to the energy function used to describe the system. The results agree with experiments. The squared correlation coefficient of the calculated vs. the measured values is 0.79. The sampling scheme consists of a series of molecular dynamics integrations with biases. The biases are selected based on an estimate of the probability density function of the system in a way to explore the conformational space and to reduce the statistical error in the calculated binding constants. The molecular dynamics integrations are done with a vacuum potential using a short cutoff scheme. To estimate the probability density of the simulated system, the results of the molecular dynamics integrations are combined using an extension of the weighted histogram analysis method (C. Bartels, Chem. Phys. Letters 331 (2000) 446-454). The probability density of the solvated ligand-protein system is obtained by applying a correction for the use of the short cutoffs in the simulations and by taking into account solvation with an electrostatic term and a hydrophobic term. The electrostatic part of the solvation is determined by finite difference Poisson-Boltzmann calculations; the hydrophobic part of the solvation is set proportional to the solvent accessible surface area. Setting the hydrophobic surface tension parameter equal to 8 mol(-1) K(-1) A(-2), absolute binding constants are in the muM to nM range. This is in agreement with experiments. The standard errors determined from eight repeated binding constant determinations are a factor of 14 to 411. A single determination of a binding constant is done with 499700 steps of molecular dynamics integration and 4500 finite difference Poisson-Boltzmann calculations. The simulations can be analyzed with respect to conformational changes of the active site of the HIV-1 protease or the ligands upon binding and provide information that complements experiments and can be used in the drug development process.