Photoredox-Mediated Hydrogen Isotope Exchange Reactions of Amino-Acids,Peptides, and Peptide-Derived Drugs

Hydrogen isotopically labelled compounds are essential diagnostic tools in drug research and development, as they provide vital information about the biological metabolism of drug candidates and their metabolites. Herein we report a photoredox-initiated hydrogen atom transfer (HAT) protocol which efficiently and selectively introduces deuterium or tritium at C(sp³)−H bonds, utilizing heavy water (D₂O or T₂O) as the hydrogen isotope source, and a guanidine base. This protocol has been successfully applied to the incorporation of deuterium in several amino acids (lysine, glycine and proline) and small peptides. Finally, the method has been applied to tritium, because tritium-labelled peptides are essential for application in biological experiments, such as ligand-binding assays, or absorption, distribution, metabolism, and excretion (ADME) studies.     

Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands†

New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H₁R, H₂R, H₃R, H₄R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 ( 2 ). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH₁R) and right atrium (gpH₂R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H₃R, S-methylisothiourea analogue 143 obtained high affinity at the hH₄R (pK_i=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.     

Wall-impinging laminar premixed n-dodecane flames under autoignitive conditions

Laminar one-dimensional (1D) flames in a stagnation flow stabilised at a wall are used to study flame–wall interaction under diesel engine conditions. The thermochemical conditions correspond to that of the Engine Combustion Network (ECN) Spray A reference case. A range of inflow velocities is considered, where the lowest inflow velocity is chosen such that the flame is detached from the inlet. The presence of a wall is shown to have a significant impact on the flame structure and emission formation. The 1D flame and homogeneous reactor results exhibit two distinct reaction zones due to low- and high-temperature chemistry (LTC and HTC, respectively). The burner-stabilised flames are overall dominated by autoignition for all inflow velocities. For the impinging jet flames, the response of the LTC reaction zone follows closely that of the burner-stabilised flames up to relatively high inflow velocities. The HTC reaction zone, however, deviates strongly from the burner-stabilised flames, already at low inflow velocities and quenches at high inflow velocities. A budget analysis revealed a strong contribution from diffusion in the HTC reaction zone, resulting in an increasing importance of deflagrative combustion as opposed to autoignition. This trend was attributed to enhanced strain rates at higher inlet velocity leading to higher gradients. Wall heat transfer was also investigated. The highest wall heat transfer rates were observed for mixtures between $\Phi =1.0$ and $\Phi =1.5$ and for inlet velocities just below the quenching limit. This was attributed jointly to the higher peak product temperatures for these mixtures and to their enhanced resilience to quenching under strain which leads to higher temperature gradients at the wall just before quenching. NO formation was studied. The highest NO formation was observed near $\Phi =1.0,$ though the response to strain rate was different for stoichiometric and rich mixtures, which was attributed to differing NO formation pathways.     

Studying nanomagnets and magnetic heterostructures with X-ray PEEM at the Swiss Light Source

Polarization dependent X-ray absorption spectroscopy and microscopy enables the element selective investigation of magnetic systems at the nanoscale. At the Swiss Light Source a photoemission electron microscope is used for the study of a broad variety of systems. Here, a review of recent activities is presented with a focus on instrumental and analytical developments. A new procedure for the 3 dimensional determination of the magnetization vector has been developed, and is demonstrated for GdFeCo microstructures displaying in-plane and out-of-plane domains, and sub-20 nm Fe nanoparticles. The recent progress for measurements in applied magnetic fields is presented and a new set-up for time-resolved measurements employing femtosecond laser pulses is described.     

Application of a multiple mapping conditioning mixing model to ECN Spray A

The engine combustion network (ECN) Spray A is modelled using the Reynolds-averaged Navier–Stokes-transported probability density function (RANS-TPDF) approach to validate the application of a new multiple mapping conditioning (MMC) mixing model to multiphase reactive flows. The composition TPDF equations are solved using a Lagrangian stochastic approach and the spray is modelled with a discrete particle approach. The model is first validated under non-reacting conditions (at 900 K) using experimental mixture-fraction data. Reactive simulations are then performed for three different ambient temperatures (800, 900, 1100 K) and oxygen concentrations (13, 15, 21%) at an ambient density of 22.8 kg/m³. The MMC mixing model is compared with the interaction by exchange with the mean (IEM) mixing model. The ignition delay predictions are not sensitive to the mixing model and are predicted well by both the mixing models under all the tested ambient conditions. The IEM model overpredicts the flame lift-off length (FLOL) at high temperature and high oxygen conditions with a mixing constant $C_{?}=2$. The MMC model with $C_{?}=2$ and a target correlation coefficient $r_t=0.935$ between the mixture fraction and a reference variable used to condition mixing predicts good FLOL under all the conditions except 800 K. It is demonstrated that the lift-off length is controllable by changing the target correlation coefficient, while C_? and therefore the mixing fields are held fixed. In comparison to the MMC model, the IEM model predicts a higher variance of temperature conditioned on mixture fraction near the flame base owing to its lacking the property of localness. The mixing distance between the notional TPDF particles in the composition space is also higher with the IEM model and it is demonstrated that by changing r_t, different levels of mixing locality can be achieved.