A quantitative LC/MS method targeting urinary 1-methyl-4-imidazoleacetic acid for safety monitoring of the global histamine turnover in clinical studies

Anaphylaxis is a potentially life-threatening condition triggered mainly by the release of inflammatory mediators, notably histamine. In pharmaceutical research, drug discovery, and clinical evaluation, it may be necessary to accurately assess the potential of a compound, event, or disorder to promote the release of histamine. In contrast to the measurement of plasma histamine, determination of the stable metabolite 1-methyl-4-imidazoleacetic acid (tele-MIAA) in urine provides a noninvasive and more reliable methodology to monitor histamine release. This study presents a repeatable high-performance liquid chromatography coupled to electrospray mass spectrometry (LC–ESI–MS) method where tele-MIAA is baseline separated from its structural isomer 1-methyl-5-imidazoleacetic acid (pi-MIAA) and an unknown in human urine. The ion-pairing chromatography method, in reversed-phase mode, based on 0.5 mM tridecafluoroheptanoic acid demonstrated high repeatability and was applied in a clinical development program that comprised a large number of clinical samples from different cohorts. The inter- and intra-run precision of the method for tele-MIAA were 8.4 and 4.3 %, respectively, at the mean urinary concentration level, while method accuracy was between ?16.2 and 8.0 % across the linear concentration range of 22–1,111 ng mL^?1. Overall, method precision was greater than that reported in previously published methods and enabled the identification of gender differences that were independent of age or demography. The median concentration measured in female subjects was 3.0 μmol mmol^?1 of creatinine, and for male subjects, it was 2.1 μmol mmol^?1 of creatinine. The results demonstrate that the method provides unprecedented accuracy, precision, and practicality for the measurement of tele-MIAA in large clinical settings.

Anticancer Aminoferrocene Derivatives Inducing Production of Mitochondrial Reactive Oxygen Species

Elevated levels of reactive oxygen species (ROS) and deficient mitochondria are two weak points of cancer cells. Their simultaneous targeting is a valid therapeutic strategy to design highly potent anticancer drugs. The remaining challenge is to limit the drug effects to cancer cells without affecting normal ones. We have previously developed three aminoferrocene (AF)-based derivatives, which are activated in the presence of elevated levels of ROS present in cancer cells with formation of electron-rich compounds able to generate ROS and reduce mitochondrial membrane potential (MMP). All of them exhibit important drawbacks including either low efficacy or high unspecific toxicity that prevents their application in vivo up to date. Herein we describe unusual AF-derivatives lacking these drawbacks. These compounds act via an alternative mechanism: they are chemically stable in the presence of ROS, generate mitochondrial ROS in cancer cells, but not normal cells and exhibit anticancer effect in vivo.     

A Comparison of Four Different Electrode Matrices on the Performance of Amperometric Hydrogen Peroxide (Bio)Sensors

A comparison of the analytical performances of four different (bio)sensor designs in H₂O₂ determination is discussed. The (bio)sensor designs developed were based on the use of (i) multiwalled carbon nanotubes (MWCNT), zinc oxide nanoparticles (ZnONP), prussian blue (PB); (ii) MWCNT, ZnONP, PB and ionic liquid (IL); (iii) MWCNT, ZnONP and horseradish peroxidase (HRP) and (iv) MWCNT, ZnONP, HRP and IL modified glassy carbon electrode (GCE). A performance comparison of (bio)sensors showed that the one based on HRP/IL-MWCNT-ZnONP/GCE showed the best analytical characteristics with a linear dynamic range of 9.99×10⁻⁸–7.55×10⁻⁴ M, detection limit of 1.37×10⁻⁸ M and sensitivity of 17.00 μA mM⁻¹.     

Reactivities of mixed organozinc and mixed organocopper reagents. Part 13 Kinetic study for phosphine‐catalyzed acylation of alkylarylzincs and effect of residual group on the transfer rate of alkyl group

Kinetics of reactions of di‐n‐butylzinc, n‐Bu₂Zn, and mixed n‐butyl(substituted phenyl)zinc reagents and n‐Bu(functional group (FG)?C₆H₄)Zn with benzoyl chloride in the presence of tri‐n‐butylphosphine have been investigated. Reaction rates of transferable n‐butyl group have been determined in tetrahydrofuran at 0 °C to compare the transfer rate of n‐butyl group in homo and mixed diorganozincs. Rate law is consistent with a third‐order reaction, which is first order in diorganozinc, benzoyl chloride, and n‐Bu₃P, and a mechanism was proposed. The lower reaction rate of n‐BuPhZn than that of n‐Bu₂Zn and negative reaction constant in Hammett plot are in accordance with the carbanionic charge of transferable n‐butyl group in the acylation reaction. These findings support the hypothesis that the reaction rate of transferable group, R_T, changes depending upon the residual group, R_R, in R_RR_TZn reagents. Copyright © 2016 John Wiley & Sons, Ltd.     

Probing the Local Reaction Environment During High Turnover Carbon Dioxide Reduction with Ag-Based Gas Diffusion Electrodes

Discerning the influence of electrochemical reactions on the electrode microenvironment is an unavoidable topic for electrochemical reactions that involve the production of OH⁻ and the consumption of water. That is particularly true for the carbon dioxide reduction reaction (CO₂RR), which together with the competing hydrogen evolution reaction (HER) exert changes in the local OH⁻ and H₂O activity that in turn can possibly affect activity, stability, and selectivity of the CO₂RR. We determine the local OH⁻ and H₂O activity in close proximity to a CO₂-converting Ag-based gas diffusion electrode (GDE) with product analysis using gas chromatography. A Pt nanosensor is positioned in the vicinity of the working GDE using shear-force-based scanning electrochemical microscopy (SECM) approach curves, which allows monitoring changes invoked by reactions proceeding within an otherwise inaccessible porous GDE by potentiodynamic measurements at the Pt-tip nanosensor. We show that high turnover HER/CO₂RR at a GDE lead to modulations of the alkalinity of the local electrolyte, that resemble a 16 m KOH solution, variations that are in turn linked to the reaction selectivity.     

Synergistic Effect of Lithium Perchlorate and Sodium Hydroxide in the Preparation of Electrochemically Treated Pencil Graphite Electrodes for Selective and Sensitive Bisphenol A Detection in Water Samples

In this study, pencil graphite electrodes were activated electrochemically in the presence of different supporting electrolytes and used for the selective and sensitive determination of bisphenol A (BPA) in water samples. Synergistic effects of both LiClO₄ and NaOH supporting electrolytes on the performance of the electrochemically treated pencil graphite electrode (ETPGE) were demonstrated in the oxidation of BPA. The electrochemical behavior of BPA on the ETPGE showed two irreversible oxidation peaks at 0.744 V and 0.877 V (vs. SCE). The detection limit was determined to be 3.1 nM. This single‐use electrode is a very promising candidate to overcome the passivation problems arising from the oxidation of BPA. The analytical application of the ETPGE was performed in tap and river water samples.     

Strong ionic interactions in noncovalent complexes between poly(ethylene imine), a cationic electrolyte,and Cibacron Blue,a nucleotide mimic – implications for oligonucleotide vectors

Cationic polymers can bind DNA to form polyplexes, which are noncovalent complexes used for gene delivery into the targeted cells. For more insight on such biologically relevant systems, the noncovalent complexes between the cationic polymer poly(ethylene imine) (PEI) and the nucleotide mimicking dye Cibacron Blue F3G‐A (CB) were investigated using mass spectrometry methods. Two PEIs of low molecular weight were utilized (M_n ≈ 423 and 600 Da). The different types of CB anions produced by Na⁺/H⁺ exchanges on the three sulfonic acid groups of CB and their dehydrated counterparts were responsible for complex formation with PEI. The CB anions underwent noncovalent complex formation with protonated, but not with sodiated PEI. A higher proportion of cyclic oligomers were detected in PEI423 than PEI600, but both architectures formed association products with CB. Tandem mass spectrometry studies revealed a significantly stronger noncovalent interaction between PEI and dehydrated CB than between PEI and intact CB. Copyright © 2014 John Wiley & Sons, Ltd.     

Improvements of Tolerance to Stress Conditions by Genetic Engineering in Saccharomyces Cerevisiae during Ethanol Production

Saccharomyces cerevisiae, industrial yeast isolate, has been of great interest in recent years for fuel ethanol production. The ethanol yield and productivity depend on many inhibitory factors during the fermentation process such as temperature, ethanol, compounds released as the result of pretreatment procedures, and osmotic stress. An ideal strain should be able to grow under different stress conditions occurred at different fermentation steps. Development of tolerant yeast strains can be achieved by reprogramming pathways supporting the ethanol metabolism by regulating the energy balance and detoxicification processes. Complex gene interactions should be solved for an in-depth comprehension of the yeast stress tolerance mechanism. Genetic engineering as a powerful biotechnological tool is required to design new strategies for increasing the ethanol fermentation performance. Upregulation of stress tolerance genes by recombinant DNA technology can be a useful approach to overcome inhibitory situations. This review presents the application of several genetic engineering strategies to increase ethanol yield under different stress conditions including inhibitor tolerance, ethanol tolerance, thermotolerance, and osmotolerance.     

Synthesis of the 8,19-Epoxysteroid Eurysterol A

We report the first chemical synthesis of eurysterol A, a cytotoxic and antifungal marine steroidal sulfate with a unique C8−C19 oxy-bridged cholestane skeleton. After C19 hydroxylation of cholesteryl acetate, used as an inexpensive commercial starting material, the challenging oxidative functionalization of ring B was achieved by two different routes to set up a 5α-hydroxy-7-en-6-one moiety. As a key step, an intramolecular oxa-Michael addition was exploited to close the oxy-bridge (8β,19-epoxy unit). DFT calculations show this reversible transformation being exergonic by about −30 kJ mol⁻¹. Along the optimized (scalable) synthetic sequence, the target natural product was obtained in only 11 steps in 5 % overall yield. In addition, an access to (isomeric) 7β,19-epoxy steroids with a previously unknown pentacyclic ring system was discovered.     

Crystal Structure and Computational Study of 5-Ethyl-4-(4-Methoxyphenethyl)-4,5-Dihydro-3H-1,2,4-Triazol-3-One and 4-(4-Methoxyphenethyl)-5-Propyl-4,5-Dihydro-3H-1,2,4-Triazol-3-One

Crystallography Reports - Molecular structures of compounds 5-ethyl-4-(4-methoxyphenethyl)-4,5-dihydro-3H-1,2,4-triazol-3-one, (C13H17N3O2) (I) and...