Cycloaddition Reactions of the Metal Phosphorus Double Bonded Complexes CP(CO)2M=PR2 (M = MO,W; R = Alkyl,Aryl)

Abstract

The reaction of the metal phosphorus double bonded species Cp(CO)₂M=PR₂ (M = Mo, W; R = aryl, alkyl) (1)¹⁾ with diverse diazoalkanes, alkenes, alkines and dienes results in the facile formation of the [2+1]-, [2+2]1- and [2+4]-cycloaddition products 2a-c.     

Separation of 9 Sulfonamide Drugs in ≈4 Min by Ultra-High Performance Supercritical Fluid Chromatography (UHPSFC): with a Feasibility Study for Detection in Milk

Nine widely used veterinary sulfonamide drugs were baseline separated (R _s ≥1.5) in just over 4 min using a 3 × 100 mm, 1.8 μm RX-Sil column, with 9.2 % methanol in carbon dioxide, at 110 bar and 30 °C, with direct UV detection at 260 nm using a 3 mm, 2 μL tapered flow cell. Pressure drop was only 172 bar. Optimization was difficult due to the similarity in structures. Small changes in modifier concentration, temperature and pressure, each tended to improve the resolution of some peak pairs but degraded the resolution of others. There were four critical pairs, each responding differently to changes in conditions. Optimization was performed by plotting resolution between pairs as a function of modifier concentration first, temperature second, and outlet pressure third. Retention time was then minimized by changing flow rate. The estimated limit of quantitation (LOQ, S/N >10), for direct injections, was ≈200–400 ng/g of each, inadequate for regulatory requirements. Solid phase extraction (SPE) attempted to pre-concentrate samples spiked with sulfamethazine by ≈20:1. From water, the limit of detection (LOD) was ≈2.7 ng/mL with LOQ ≈9 ng/mL using UV at 260 nm. The LOD for milk was 6.2 ng/mL, and LOQ was 20.1 ng/mL. A better pre-concentration step or a more sensitive detector such as MS–MS is required. Even with these inadequacies, SFC was shown to be a feasible, faster, “greener” alternative to HPLC for the separation of these drugs.     

Photokinetic,Biochemical and Structural Features of Chimeric Photoactive Yellow Protein Constructs

Of the 10 photoactive yellow protein (PYPs) that have been characterized, the two from Rhodobacter species are the only ones that have an additional intermediate spectral form in the resting state (λ_max = 375 nm), compared to the prototypical Halorhodospira halophila PYP. We have constructed three chimeric PYP proteins by replacing the first 21 residues from the N‐terminus (Hyb1PYP), 10 from the β4–β5 loop (Hyb2PYP) and both (Hyb3PYP) in Hhal PYP with those from Rb. capsulatus PYP. The N‐terminal chimera behaves both spectrally and kinetically like Hhal PYP, indicating that the Rcaps N‐terminus folds against the core of Hhal PYP. A small fraction shows dimerization and slower recovery, possibly due to interaction at the N‐termini. The loop chimera has a small amount of the intermediate spectral form and a photocycle that is 20 000 times slower than Hhal PYP. The third chimera, with both regions exchanged, resembles Rcaps PYP with a significant amount of intermediate spectral form (λ_max = 380 nm), but has even slower kinetics. The effects are not strictly additive in the double chimera, suggesting that what perturbs one site, affects the other as well. These chimeras suggest that the intermediate spectral form has its origins in overall protein stability and solvent exposure.     

Novel Methods to Manipulate Autolysis in Sparkling Wine: Effects on Yeast

Sparkling wine made by the traditional method (Méthode Traditionelle) develops a distinct and desirable flavour and aroma profile attributed to proteolytic processes during prolonged ageing on lees. Microwave, ultrasound and addition of β-glucanase enzymes were applied to accelerate the disruption of Saccharomyces cerevisiae, and added to the tirage solution for secondary fermentation in traditional sparkling winemaking. Scanning electron microscopy and flow cytometry analyses were used to observe and describe yeast whole-cell anatomy, and cell integrity and structure via propidium iodide (PI) permeability after 6-, 12- and 18-months post-tirage. Treatments applied produced features on lees that were distinct from that of the untreated control yeast. Whilst control yeast displayed budding cells (growth features) with smooth, cavitated and flat external cell appearances; microwave treated yeast cells exhibited modifications like ‘doughnut’ shapes immediately after treatment (time 0). Similar ‘doughnut’-shaped and ‘pitted/porous’ cell features were observed on progressively older lees from the control. Flow cytometry was used to discriminate yeast populations; features consistent with cell disruption were observed in the microwave, ultrasound and enzyme treatments, as evidenced by up to 4-fold increase in PI signal in the microwave treatment. Forward and side scatter signals reflected changes in size and structure of yeast cells, in all treatments applied. When flow cytometry was interpreted alongside the scanning electron microscopy images, bimodal populations of yeast cells with low and high PI intensities were revealed and distinctive ‘doughnut’-shaped cell features observed in association with the microwave treatment only at tirage, that were not observed until 12 months wine ageing in older lees from the control. This work offers both a rapid approach to visualise alterations to yeast cell surfaces and a better understanding of the mechanisms of yeast lysis. Microwave, ultrasound or β-glucanase enzymes are tools that could potentially initiate the release of yeast cell compounds into wine. Further investigation into the impact of such treatments on the flavour and aroma profiles of the wines through sensory evaluation is warranted.     

Z = 50 shell gap near 100Sn from intermediate-energy Coulomb excitations in even-mass 106-112Sn isotopes

Rare isotope beams of neutron-deficient 106,108,110Sn from the fragmentation of 124Xe were employed in an intermediate-energy Coulomb excitation experiment. The measured B(E2,0(1)(+)-->2(1)(+)) values for 108Sn and 110Sn and the results obtained for the 106Sn show that the transition strengths for these nuclei are larger than predicted by current state-of-the-art shell-model calculations. This discrepancy might be explained by contributions of the protons from within the Z = 50 shell to the structure of low-energy excited states in this region.     

Direct Oxidative Coupling of N‐Acetyl Indoles and Phenols for the Synthesis of Benzofuroindolines Related to Phalarine

Inspired by the biogenetic synthesis of benzofuroindoline‐containing natural products, we designed an oxidative coupling between phenol and N‐acetyl indoles. This straightforward and direct radical process, mediated by 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone and FeCl₃ allowed the regioselective synthesis of benzofuro[3,2‐b]indolines, whose structure is found in the natural product phalarine.     

D3R grand challenge 4: blind prediction of protein–ligand poses,affinity rankings,and relative binding free energies

Journal of Computer-Aided Molecular Design - The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and...     

The impact of stochastic lead time reduction on inventory cost under order crossover

We use exponential lead times to demonstrate that reducing mean lead time has a secondary reduction of the variance due to order crossover. The net effect is that of reducing the inventory cost, and if the reduction in inventory cost overrides the investment in lead time reduction, then the lead time reduction strategy would be tenable.We define lead time reduction as the process of decreasing lead time at an increased cost. To date, decreasing lead times has been confined to deterministic instances. We examine the case where lead times are exponential, for when lead times are stochastic, deliveries are subject to order crossover, so that we must consider effective lead times rather than the actual lead times. The result is that the variance of these lead times is less than the variance of the original replenishment lead times.Here we present a two-stage procedure for reducing the mean and variance for exponentially distributed lead times. We assume that the lead time is made of one or several components and is the time between when the need of a replenishment order is determined to the time of receipt.     

Cyclosporin Measurement – who cares about inaccuracy?

Most medical laboratories measure the immunosuppressive drug cyclosporin using one of a number of commercial immunoassays, or high-performance liquid chromatography (HPLC). The calibration of these assays is based on material supplied by the kit manufacturers or prepared in-house. We have examined inaccuracy for the measurement of cyclosporin in samples spiked to known concentrations and the impact of any inaccuracy on the results for cyclosporin measurement in pooled samples from patients prescribed the drug. The data were from the International Cyclosporin Proficiency Testing Scheme, based on aliquots of cyclosporin-free blood to which known amounts of the drug had been added or aliquots of pooled samples collected from patients receiving cyclosporin. Compared with the results using HPLC, the immunoassays had a median bias which ranged from –4.5% to 8.2% for the spiked samples. When pooled samples from patients were analysed the percentage difference from the measured HPLC value, allowing for assay inaccuracy, was as high as 29.9%. It is concluded that inaccuracy is a factor in between-assay performance for this measurement and that proficiency testing schemes should attempt to put more emphasis on this aspect of assay performance.