Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Experimental and numerical analysis of the influence of cable tray arrangements on the resulting mass loss rate and fire spreading

In the context of industrial buildings and power plants, electrical installations and cable trays represent a main fuel load and a potential initial fire source due to possible short circuits or comparable malfunction. Furthermore, a fire can spread from one tray to additional trays mounted above and/or horizontally on one tray. Because of the high significance of cable fires, several research projects have been carried out, investigating the fire behaviour of cables from small‐scale tests, eg, the cone calorimeter, up to large‐scale tests, analysing complete cable tray constructions. The goal of the work presented in this paper is the extension of the knowledge regarding the influence of geometrical parameters like the packing density and tray distance on the burning behaviour and fire spread of cable tray installations. The results are considered, together with test results from the literature, to quantify the main physical parameters describing the burning behaviour. In a next step, the general applicability of these parameters as input data for the parametrization of the source term of numerical simulations is shown. The test results show that the burning behaviour and the fire spreading highly depend on the cable arrangement of the cables on the cable tray, in combination with other boundary conditions. By applying the results as input for a fire simulation, the mass loss rate is considered appropriately.     

Dielectric relaxation of vegetable-based polyurethane

Vegetable-based polyurethane (PU) was prepared in the thin film form by spin coating. This polymer is synthesised from castor oil, which can be extracted from the seeds of a native plant in Brazil called mamona. This polymer is biocompatible and is being used as material for artificial bone. The PU was characterised by dielectric spectroscopy in a wide range of frequency (10^–5 Hz to 10⁵ Hz) and by thermally stimulated discharge current (TSDC) measurements. The glass transition temperature (T _g = 39°C) was determined and using the initial rise method the activation energy was found to be 1.58 eV.     

Comparison of single-fiber and macro electrode recordings: relationship to motor unit action potential duration

The factors contributing to the duration of a motor unit action potential (MUAP) are believed to be well known, with both manual measurements and computer simulations agreeing with respect to MUAP durations approaching 10 ms. In this investigation, it is clearly demonstrated that use of a wide-open amplifier bandpass combined with signal-to-noise ratio enhancement results in MUAP durations approaching 30 ms recorded with either a macro or single-fiber electrode. Why the clinically recorded MUAP duration differs significantly from these physiologic durations is discussed. A hypothesis is presented whereby the major contributing factor toward MUAP duration is the total time of action potential transmembrane current flow along the muscle fiber from end-plate zone to musculotendinous junction.     

Clarification of a wheat straw‐derived medium with ion‐exchange resins for xylitol crystallization

BACKGROUND: Xylitol bioproduction from lignocellulosic residues comprises hydrolysis of the hemicellulose, detoxification of the hydrolysate, bioconversion of the xylose, and recovery of xylitol from the fermented hydrolysate. There are relatively few reports on xylitol recovery from fermented media. In the present study, ion‐exchange resins were used to clarify a fermented wheat straw hemicellulosic hydrolysate, which was then vacuum‐concentrated and submitted to cooling in the presence of ethanol for xylitol crystallization. RESULTS: Sequential adsorption into two anion‐exchange resins (A‐860S and A‐500PS) promoted considerable reductions in the content of soluble by‐products (up to 97.5%) and in medium coloration (99.5%). Vacuum concentration led to a dark‐colored viscous solution that inhibited xylitol crystallization. This inhibition could be overcome by mixing the concentrated medium with a commercial xylitol solution. Such a strategy led to xylitol crystals with up to 95.9% purity. The crystallization yield (43.5%) was close to that observed when using commercial xylitol solution (51.4%). CONCLUSION: The experimental data demonstrate the feasibility of using ion‐exchange resins followed by cooling in the presence of ethanol as a strategy to promote the fast recovery and purification of xylitol from hemicellulose‐derived fermentation media. Copyright © 2008 Society of Chemical Industry     

,,Rich Internet Applications“ – Eine perfekte Kombination benutzerfreundlicher Schnittstellen mit Webtechnologie

Zusammenfassung  ,,Rich Internet Applications“ (RIA) sind Webapplikationen, die mit einer wesentlich interaktiveren Benutzerschnittstelle ausgestattet sind, als wir das bisher von den auf HTML basierten ,,poor ugly web applications“ (PUWA) gewohnt waren.     

The effects of a monetary alternative on marijuana self-administration

We have used a variety of methods to characterize the genome of the archaeon Methanosarcina thermophila TM-1. Pulsed-field gel analysis indicates a genome size of 2.8 Mb. We have constructed a bacterial artificial chromosome (BAC) library of M. thermophila and have used it to generate physical maps for this organism. The library is made up of 384 clones with an average insert size of 58 kb representing 8.0 genome equivalents. The utility of the library for low-resolution physical mapping was shown by identifying NotI linking clones and using these to order the NotI macrorestriction fragments of M. thermophila into a 2.8 Mb map. Hybridization of nine single copy genes and a 16S rRNA sequence to these macrorestriction fragments forms the basis for the first genetic map in this organism. High-resolution physical maps, consisting of overlapping clones, have been created using HindIII fingerprints of BAC clones. In this way, we identified a minimal path of five clones that span a 270 kb NotI fragment. The ease of manipulating BAC clones makes the BAC system an excellent choice for the construction of low-resolution and high-resolution physical and genetic maps of archaeal genomes. It also provides a substrate for future genome-sequencing efforts.