Construction of diverse peptide structural architectures via chemoselective peptide ligation

Herein, we report the development of a facile synthetic strategy for constructing diverse peptide structural architectures via chemoselective peptide ligation. The key advancement involved is to utilize the benzofuran moiety as the peptide salicylaldehyde ester surrogate, and Dap–Ser/Lys–Ser dipeptide as the hydroxyl amino functionality, which could be successfully introduced at the side chain of peptides enabling peptide ligation. With this method, the side chain-to-side chain cyclic peptide, branched/bridged peptides, tailed cyclic peptides and multi-cyclic peptides have been designed and successfully synthesized with native peptidic linkages at the ligation sites. This strategy has provided an alternative strategic opportunity for synthetic peptide development. It also serves as an inspiration for the structural design of PPI inhibitors with new modalities.

Methods of introducing peptide salicylaldehyde esters and hydroxyl amine functionality into the peptide side chain have been developed. Diverse peptide structural motifs were constructed via ligation with native amide linkages at the ligation sites.     

Dimethocaine,a synthetic cocaine analogue: studies on its in-vivo metabolism and its detectability in urine by means of a rat model and liquid chromatography–linear ion-trap (high-resolution) mass spectrometry

Dimethocaine (DMC, larocaine), a synthetic derivative of cocaine, is a widely distributed “legal high” consumed as a “new psychoactive substance” (NPS) without any safety testing, for example studies of metabolism. Therefore, the purpose of this work was to study its in-vivo and in-vitro metabolism by use of liquid chromatography–(high resolution) mass spectrometry (LC–HRMS ⁿ ). DMC was administered to male Wistar rats (20 mg kg^?1) and their urine was extracted either by solid-phase extraction after enzymatic cleavage of conjugates or by use of protein precipitation (PP). The metabolites were separated and identified by LC–HRMS ⁿ . The main phase I reactions were ester hydrolysis, deethylation, hydroxylation of the aromatic system, and a combination of these. The main phase II reaction was N-acetylation of the p-aminobenzoic acid part of the unchanged parent compound and of several phase I metabolites. The metabolites identified were then used for identification of DMC in rat urine after application of a common user’s dose. By use of GC–MS and LC–MS ⁿ standard urine-screening approaches (SUSAs), DMC and its metabolites could be detected in the urine samples.     

A stress-velocity least-squares mixed finite element formulation for incompressible elastodynamics

In the framework of solving elastodynamic problems using a least-squares mixed finite element method (LSFEM) the implementation of a stress-velocity formulation for small strains is introduced and discussed in the present contribution. The element formulation is based on a first-order div – grad system, with the balance equation of momentum and the constitutive law as the governing equations. Application of the L₂-norm to the two residuals leads to a functional depending on stresses and velocities. Different time discretization schemes are considered, a scalar weighting is introduced and chosen in dependency of the different time discretization methods. In a numerical example the influence of the time integration method, the chosen time step width and the related weighing factor are investigated for a two-dimensional problem. (© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Understanding the Chloride Affinity of Barbiturates for Anion Receptor Design

Due to their potential binding sites, barbituric acid (BA) and its derivatives have been used in metal coordination chemistry. Yet their abilities to recognize anions remain unexplored. In this work, we were able to identify four structural features of barbiturates that are responsible for a certain anion affinity. The set of coordination interactions can be finely tuned with covalent decorations at the methylene group. DFT-D computations at the BLYP-D3(BJ)/aug-cc-pVDZ level of theory show that the C−H bond is as effective as the N−H bond to coordinate chloride. An analysis of the electron charge density at the C−H⋅⋅⋅Cl⁻ and N−H⋅⋅⋅Cl⁻ bond critical points elucidates their similarities in covalent character. Our results reveal that the special acidity of the C−H bond shows up when the methylene group moves out of the ring plane and it is mainly governed by the orbital interaction energy. The amide and carboxyl groups are the best choices to coordinate the ion when they act together with the C−H bond. We finally show how can we use this information to rationally improve the recognition capability of a small cage-like complex that is able to coordinate NaCl.     

Correcting saturation effects of the arterial input function in dynamic susceptibility contrast-enhanced MRI: a Monte Carlo simulation

To prevent systematic errors in quantitative brain perfusion studies using dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI), a reliable determination of the arterial input function (AIF) is essential. We propose a novel algorithm for correcting distortions of the AIF caused by saturation of the peak amplitude and discuss its relevance for longitudinal studies. The algorithm is based on the assumption that the AIF can be separated into a reliable part at low contrast agent concentrations and an unreliable part at high concentrations. This unreliable part is reconstructed, applying a theoretical framework based on a transport-diffusion theory and using the bolus-shape in the tissue. A validation of the correction scheme is tested by a Monte Carlo simulation. The input of the simulation was a wide range of perfusion, and the main aim was to compare this input to the determined perfusion parameters. Another input of the simulation was an AIF template derived from in vivo measurements. The distortions of this template was modeled via a Rician distribution for image intensities. As for a real DSC-MRI experiment, the simulation returned the AIF and the tracer concentration-dependent signal in the tissue. The novel correction scheme was tested by deriving perfusion parameters from the simulated data for the corrected and the uncorrected case. For this analysis, a common truncated singular value decomposition approach was applied. We find that the saturation effect caused by Rician-distributed noise leads to an overestimation of regional cerebral blood flow and regional cerebral blood volume, as compared to the input parameter. The aberration can be amplified by a decreasing signal-to-noise ratio (SNR) or an increasing tracer concentration. We also find that the overestimation can be successfully eliminated by the proposed saturation-correction scheme. In summary, the correction scheme will allow DSC-MRI to be expanded towards higher tracer concentrations and lower SNR and will help to increase the measurement to measurement reproducibility for longitudinal studies.