An investigation into the one-pot Heck olefination-hydrogenation reaction

Herein is described an operationally simple process concerning the observation that, following either inter-, or intramolecular Heck olefination, stirring of the so formed substituted alkenyl product under an atmosphere of hydrogen efficiently effects alkene hydrogenation. Overall this two-operation, one-pot "reductive Heck" sequence is notable since direct reductive Heck processes, using additives such as formate salts, are restricted to a limited range of substrates. In total 25 examples are reported (yields ranging from 0 to 95%), which were selected in order to probe the scope and limitations of this method. Finally, the utility of this sequence was demonstrated in a short synthesis of the calcimimetic agent, cinacalcet.     

Human cytokines characterized by dielectric thermal analysis, thermogravimetry, and differential scanning calorimetry

Malaria affects over 500 million people worldwide leading to 1–2 million deaths each year, the majority of whom are children. Four Plasmodium species cause malaria in humans. To properly diagnose, and correctly treat malarial infections, accurate diagnosis of infection is required. Proper diagnosis of infection will result in a reduction of morbidity, mortality, and of drug resistant parasites. However, the current tests for malaria diagnosis do not efficiently identify the appropriate human and parasite biomarkers associated with disease. Detection of specific inflammatory mediators such as cytokines associated with malaria pathogenesis will aid the determination of disease progression, disease prognosis, and the early diagnosis of malaria infection. In this study, we used dielectric thermal analysis (DETA), thermogravimetric analysis, and differential scanning calorimetry (DSC) to characterize five human cytokines (IL-1α, IL-2, IL-4, IL-6, and IL-10), to demonstrate how their thermoanalytical properties can be investigated for sensor design. Analysis for DETA was performed at a frequency range of 0.1–300,000 Hz. Permittivity and loss factor measurements were used to calculate tan δ values. Peak frequencies were used to determine dielectric signatures for each cytokine. The peak frequencies were different for each cytokine analyzed. In addition, activation energies were frequency dependent for IL-2 but frequency independent for the remaining four cytokines. Cytokines were also examined using DSC which established variance in heat of crystallization and heat of fusion of solvent among the five cytokines. A noticeable differentiation was observed with IL-1α among the other four cytokines when analyzed using trend analysis. Detection of unique dielectric signals will aid development of sensitive dielectric sensors capable of detecting cytokines in various human samples.     

Intermolecular interactions in (arene)chromium carbonyl compounds: prediction of chiral crystal packing from racemate structure

Six X-ray crystal structures are reported, all containing substituted triphenylmethanol derivative 4 either alone or as its mono or bis(chromium tricarbonyl) complexes. All four chromium complexes studied crystallize with two independent molecules in the crystallographic asymmetric unit. It is demonstrated that from the X-ray crystal structure of the acentric racemic (+/-)-(1pR,1' 'R)(1pS,1' 'S)-[Cr(CO)(3)(eta(6)-t-BuC(6)H(3)(CMeOMe)CPh(2)OH)], (+/-)-3, it is possible to deduce the 4-fold helical structure of the chiral (-)-(1pR,1' 'R) isomer, (-)-3. The bimetallic derivatives demonstrate the ability to control intermolecular interactions by the positioning of relative stereochemistry.     

Validation of a robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of navitoclax

The Bcl-2 family small molecule inhibitor navitoclax is being clinically evaluated to treat multiple cancers including lymphoid malignancies and small cell lung cancer. A sensitive and reliable method was developed to quantitate navitoclax in human plasma using liquid chromatography with tandem mass spectrometry with which to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of navitoclax and the internal standard, navitoclax-d8, was achieved with a Waters Acquity UPLC BEH C₁₈ column using isocratic flow over a 3 min total analytical run time. A SCIEX 4500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of navitoclax. The assay range was 5–5,000 ng/ml and proved to be accurate (89.5–104.9%) and precise (CV ≤ 11%). Long-term frozen plasma stability for navitoclax at −70°C was at least 43 months. The method was applied for the measurement of total plasma concentration of navitoclax in a patient receiving a 250 mg daily oral dose.     

Effects of Roxadustat on Erythropoietin Production in the Rat Body

Anemia is a major complication of chronic renal failure. To treat this anemia, prolylhydroxylase domain enzyme (PHD) inhibitors as well as erythropoiesis-stimulating agents (ESAs) have been used. Although PHD inhibitors rapidly stimulate erythropoietin (Epo) production, the precise sites of Epo production following the administration of these drugs have not been identified. We developed a novel method for the detection of the Epo protein that employs deglycosylation-coupled Western blotting. With protein deglycosylation, tissue Epo contents can be quantified over an extremely wide range. Using this method, we examined the effects of the PHD inhibitor, Roxadustat (ROX), and severe hypoxia on Epo production in various tissues in rats. We observed that ROX increased Epo mRNA expression in both the kidneys and liver. However, Epo protein was detected in the kidneys but not in the liver. Epo protein was also detected in the salivary glands, spleen, epididymis and ovaries. However, both PHD inhibitors (ROX) and severe hypoxia increased the Epo protein abundance only in the kidneys. These data show that, while Epo is produced in many tissues, PHD inhibitors as well as severe hypoxia regulate Epo production only in the kidneys.     

Heterocyclic Rearrangement of 4,5,6,7-Tetrahydro-6,6-dimethyl-benzo[c][1,2,5]oxadiazol-4-one (Z)-Arylhydrazones into Corresponding 2-Aryl-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazol-4-one Oximes

The thermal base-catalysed and photochemical transformation (Boulton-Katritzky rearrangement) of the title tetrahydrobenzo[c][1,2,5]oxadiazoles to tetrahydro-2H-benzo[d][1,2,3]triazoles is studied. Attempts to induce analogous rearrangement in tetrahydro-2H-benzo[d][1,2,3]triazol-4-one arylhydrazones or oximes failed. Some CNDO/2 calculation are also carried out.