A fluorine scan of non-peptidic inhibitors of neprilysin: Fluorophobic and fluorophilic regions in an enzyme active site

This article describes the synthesis and in vitro biological affinities of (poly)fluorinated neprilysin inhibitors. Two series of inhibitors with F-substitution of the central benzimidazole platform of the ligands and the benzylic vector to fill the S1’ pocket of NEP were investigated. The S1’ pocket was found to be highly fluorophobic, and F-substitution led to significantly decreased binding affinities of inhibitors. This result is explained by electrostatically unfavorable close contacts of organic fluorine with the negatively polarized π-surfaces of surrounding aromatic amino acid side chains. In contrast, the protein environment around the benzimidazole platform, with three electropositive guanidinium side chains of Arg residues, was found to provide a fluorophilic environment. Overall, the data support that organic fluorine, with its high negative charge density prefers to orient into electropositive regions of receptor sites. pK_a measurements of fluorinated ligands provided several simple patterns for the prediction of pK_a values of benzimidazoles, important building blocks in medicinal chemistry.     

Neuere Tendenzen in der Körperfarbenfabrikation

Ohne Zusammenfassung     

Hydroxydsysteme in Eisenoxydfarben

Zusammenfassung Es wird gezeigt, da? die durch die Namen B?hme, Hüttig, Simon, Kurnakow und Enk gemachten Beobachtungen bezüglich der Alterungsvorg?nge der Eisenhydroxyde und der Aluminium-Kiesels?urehydratsysteme auch auf die gelben Eisenfarben übertragbar sind und nutzbringend zu deren systematischer Unterscheidung angewandt werden k?nnen. Es wird weiter gezeigt, da? sich auch unter den technischen gelben Eisenfarben amorphe ohne Gitterstruktur (Marsgelb) und kristalline mit Goethitgitter finden (Eisenoxydgelb, Ferritgelb). Es wird ferner gezeigt, da? kalkhaltiges Marsgelb das CaCO₃-Gitter zeigt, und das die das Goethitgitter aufweisende toskanische Terra di Siena durch Kiesels?urehydrat verkittet ist. Weiterhin wird für verwitterten Spateisenstein das Goethitgitter, für Brauneisen aus Glimmer keine Orientierung nachgewiesen. Ein Alterungsschema wird aufgestellt. Die Anwendung der azidoiden, selektiven Farbstoffadsorption zur Teilchenunterscheidung und Kennzeichnung der Ocker wird beschrieben. Der Unterschied zwischen den an amorphen Hydraten reichen deutschen Chemosorptionsockern und den gealterten kaolinitischen franz?sischen Ockern wird dargelegt. Schlie?lich wird auf den Zusammenhang der kolloidchemischen Feststellungen mit den anstrichtechnischen Eigenschaften hingewiesen.     

An experimental investigation into the kinematics of a concentrated hard-sphere colloidal suspension during Hopkinson bar evaluation at high stresses

The behavior of a concentrated, hard-sphere colloidal suspension is evaluated using the split Hopkinson pressure bar (SHPB) experimental technique. The composition of the suspension is measured using thermograviometric analysis before and after loading. This, combined with recorded pressure distributions, result in the conclusion that the suspension undergoes high rate squeezing flow. Experimental results demonstrate that the suspension exhibits shear thickening consistent with that observed in standard rotational rheometry. At sufficiently high stresses the suspension exhibits a second regime of shear thinning behavior that is consistent with elastohydrodynamic theory that incorporates the shear modulus of the particles themselves. Further increases in stress result in irreversible behavior, i.e., rather than fracturing or crushing, the particles form non-reversible agglomerates during testing. This fact is demonstrated through the use of dynamic light scattering and electron microscopy. This behavior occurs within a regime of viscous material response which is seen to occur at normal strain rates and stresses over 10⁴ s^?1 and 40 MPa, respectively.     

Bad Fields in Positive Characteristic

If there are infinitely many p-Mersenne prime numbers, thereis no bad field of positive characteristic p. 2000 MathematicsSubject Classification 03C45, 03C60.     

Fibonacci-Cayley Numbers and Repetition Patterns in Genomic DNA

Let F(k) denote the k-th Fibonacci number in the Fibonacci sequence F(0) := 0, F(1) := 1,..., F(k+1) := F(k-1)+F(k). Motivated by proposals regarding putative mechanisms that may be responsible for producing those often observed long repetitive patterns in genomic DNA, we study in this note the Fibonacci-Cayley index fc_x of positive integers x, i.e., the largest integer for which positive integers a, b with x = aF(k-1)+bF(k) exist and show that holds for the arithmetic mean of the indices of the smallest and the largest Fibonacci numbers occurring in the Zeckendorf decomposition AMS Subject Classification: 11B39, 11A99, 92D20.     

Identification of regioisomers in a series of N-substituted pyridin-4-yl imidazole derivatives by regiospecific synthesis,GC/MS,and 1H NMR

The regiospecific synthesis of 2a (Scheme 3), a novel and potent pyridinyl imidazole inhibitor of p38 MAP (mitogen-activated protein) kinase, and the regioselective preparation of its regioisomer 2b (Scheme 4) are described. Chromatographic and spectroscopic data are presented, which in this class of compounds allow the unambiguous identification of regioisomers prepared by a nonregiospecific synthetic strategy. Biological data demonstrating the importance of the correct regiochemistry for inhibition of p38 are given.     

Facile introduction of SH group on aromatic substrates via electrophilic substitution reactions

Herein, we describe a mild and efficient two-step procedure to introduce a thiol group on aromatic substrates. First, reaction with an activated sulfoxide leads to an arylsulfonium salt intermediate. Then, two successive beta-elimination-based dealkylation reactions afford the desired arylthiols in good to excellent yields.