Compound set enrichment: a novel approach to analysis of primary HTS data

The main goal of high-throughput screening (HTS) is to identify active chemical series rather than just individual active compounds. In light of this goal, a new method (called compound set enrichment) to identify active chemical series from primary screening data is proposed. The method employs the scaffold tree compound classification in conjunction with the Kolmogorov-Smirnov statistic to assess the overall activity of a compound scaffold. The application of this method to seven PubChem data sets (containing between 9389 and 263679 molecules) is presented, and the ability of this method to identify compound classes with only weakly active compounds (potentially latent hits) is demonstrated. The analysis presented here shows how methods based on an activity cutoff can distort activity information, leading to the incorrect activity assignment of compound series. These results suggest that this method might have utility in the rational selection of active classes of compounds (and not just individual active compounds) for followup and validation.     

Physical limitations of the electroluminescence mechanism in terbium-based light emitters: matrix and layer thickness dependence

The physical limits of downscaling the SiO₂ thickness of rare earth implanted metal–oxynitride–oxide–semiconductor-based light emitters are explored by investigating the drop down of the electroluminescence power efficiency with decreasing SiO₂ thickness of Tb-implanted devices. It will be experimentally shown that there is a dark zone with an extension of about 20 nm behind the injecting interface in which the hot electrons have not yet gained enough kinetic energy in order to excite the Tb³⁺ luminescence centers. In addition, replacing the host matrix SiO₂ by SiON results in a decrease of power efficiency by two orders of magnitude what is consistent with the experimental data about the hot energy distribution in these media.     

Interaction forces and molecular adhesion between pre-adsorbed poly(ethylene imine) layers

Interaction forces between pre-adsorbed layers of branched poly(ethylene imine) (PEI) of different molecular mass were studied with the colloidal probe technique, which is based on atomic force microscopy (AFM). During approach, the long-ranged forces between the surfaces are repulsive due to overlap of diffuse layers down to distances of a few nanometers, whereby regulation of the surface charge is observed. The ionic strength dependence of the observed diffuse layer potentials can be rationalized with a surface charge of 2.3 mC/m2. The forces remain repulsive down to contact, likely due to electro-steric interactions between the PEI layers. These electro-steric forces have a range of a few nanometers and appear to be superposed to the force originating from the overlap of diffuse layers. During retraction of the surfaces, erratic attractive forces are observed due to molecular adhesion events (i.e., bridging adhesion). The frequency of the molecular adhesion events increases with increasing the ionic strength. The force response of the PEI segments is dominated by rubber-like extension profiles. Strong adhesion forces are observed for low molecular mass PEI at short distances directly after separation, while for high molecular mass weaker adhesion forces at larger distances are more common. The work of adhesion was estimated by integrating the retraction force profiles, and it was found to increase with the ionic strength.     

17O nuclear quadrupole coupling constants of water bound to a metal ion: a gadolinium(III) case study

Rotational correlation times of metal ion aqua complexes can be determined from 17O NMR relaxation rates if the quadrupole coupling constant of the bound water oxygen-17 nucleus is known. The rotational correlation time is an important parameter for the efficiency of Gd3+ complexes as magnetic resonance imaging contrast agents. Using a combination of density functional theory with classical and Car-Parrinello molecular dynamics simulations we performed a computational study of the 17O quadrupole coupling constants in model aqua ions and the [Gd(DOTA)(H2O)]- complex used in clinical diagnostics. For the inner sphere water molecule in the [Gd(DOTA)(H2O)]- complex the determined quadrupole coupling parameter chi square root of (1 + eta2/3) of 8.7 MHz is very similar to that of the liquid water (9.0 MHz). Very close values were also predicted for the the homoleptic aqua ions of Gd3+ and Ca2+. We conclude that the 17O quadrupole coupling parameters of water molecules coordinated to closed shell and lanthanide metal ions are similar to water molecules in the liquid state.     

Ligand exchange and complex formation kinetics studied by NMR exemplified on fac-[(CO)3M(H2O)] (M = Mn, Tc, Re)

In this review ligand exchange and complex formation reactions on fac-[(CO)₃M(H₂O)₃]⁺ (M = Mn, Tc, Re) and on fac-[(CO)₂(NO)Re(H₂O)₃]²⁺ are presented. A variety of experimental NMR techniques are described and it is shown that sometimes combinations of techniques applied at variable temperature or variable pressure allowed to measure exchange rate constants and their activation parameters as well as thermodynamic parameters. Furthermore, the use of uncommon nuclei for NMR like ¹⁷O or ⁹⁹Tc extends considerably the range of applications especially in aqueous solutions when ¹H NMR is often not very useful.Tricarbonyl triaqua complexes of technetium(I) and rhenium(I) became important precursors for a variety of radiopharmaceuticals under development. It has been shown that the fac-[(CO)₃M]-unit is kinetically inert and that water molecules bound to it can be easily replaced. Reactivity of the Re^I complexes is one to two orders of magnitude slower than its Tc^I analogues. Furthermore, it shows a marked acidity dependence which has not been observed for Tc^I and Mn^I species.     

Säurekatalysierte Umsetzungen von 2- Vinylanilin-Derivaten mit 1-Benzyl- und 1-Methylpiperidin-4-on: Eine Elegante Synthese Neuer Polycyclischer Indol-Derivate

Acid-Catalyzed Reactions of 2-Vinylaniline Derivatives with 1-Benzyl- and 1-Methylpiperidin-4-one: An Elegant Synthesis of New Polycyclic Indole Derivatives The reaction of 2-vinylaniline derivatives with 1-benzylpiperidin-4-one or 1-methylpiperidin-4-one in toluene at temperatures between 115 and 120° with toluene-4-sulfonic acid as catalyst leads in good yields to a new class of polycyclic indole derivatives (Scheme 1, Table 1). The structure of the new diastereoisomerically pure racemic compounds 1–5 is determined by NMR-spectroscopic methods. A reaction mechanism proceeding via cyclization of enamine 9 , leading to a racemic, tricyclic reactive intermediate 10 , and subsequent intramolecular 1,5-dipolar cyclization as key steps in proposed for the formation of octahydropyrido[4′,3′:4]cyclobut[1,2-b]indoles 1–5 . The scope and limitations of the new method are discussed (see Table 2).     

Synthesis of (all-E,2R,2′R)-oscillol

Optically active (all-E,2R,2′R)-oscillol (= (all-E,2R,2′R)-3,4,3′,4′-tetradehydro-1,2,1′,2′-tetrahydro-ψ,ψ-carotene-1,2,1′,2′-tetrol; 1 ) was synthesized according to the C₁₀ + C₂₀ + C₁₀ = C₄₀ strategy, applying the Wittig reaction to couple the synthons 4 and 6 . The chiral centre was introduced by a Sharpless dihydroxylation of 3-methylbut-2-enyl 4-nitrobenzoate ( 8 ).     

Formation of large PEE domains in PEE212-PEO112 diblock copolymer monolayers: shift of the PEO-desorption transition

PEE212-PEO112 diblock copolymer monolayers are studied at the air/water interface. At large molecular areas, with X-ray reflectivity, PEE domains are observed, which are partly immersed into the water. The domain thickness increases on compression (28 to 40 A). With off-specular X-ray reflectivity, an average domain radius of 750 A is found, but there are also smaller domains. Due to these space constraints, most PEO blocks form a brush beneath the PEE domains. Only a few PEO blocks form a corona surrounding the domains and adsorb flatly onto the air/water interface. The PEO desorption transition is observed at the typical pressure of 9 mN/m, when the flatly adsorbed PEO is compressed at a domain fraction of 95%. It occurs at 6 A2/EO monomer, about half the value found for lipopolymers or diblock copolymers with NPEE approximately NPEO or NPEE < NPEO. Apparently, the thickness of the PEE domains is determined by the forces from the two interfaces, not by the PEO block, for which flat adsorption beneath the domain would be more favorable instead of formation of a PEO brush.