Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

Mycophenolic acid (MPA), a frequently used immunosuppressant, exhibits large inter‐patient pharmacokinetic variability. This study (a) developed and validated a sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for MPA and metabolites [MPA glucuronide (MPAG) and acyl‐glucuronide (AcMPAG)] in the culture medium of HepaRG cells; and (b) characterized the metabolism interaction between MPA and p‐cresol (a common uremic toxin) in this in vitro model as a potential mechanism of pharmacokinetic variability. Chromatographic separation was achieved with a C₁₈ column (4.6 × 250 mm,5 μm) using a gradient elution with water and methanol (with 0.1% formic acid and 2 mm ammonium acetate). A dual ion source ionization mode with positive multiple reaction monitoring was utilized. Multiple reaction monitoring mass transitions (m/z) were: MPA (320.95 → 207.05), MPAG (514.10 → 303.20) and AcMPAG (514.10 → 207.05). MPA‐d₃ (323.95 → 210.15) and MPAG‐d₃ (517.00 → 306.10) were utilized as internal standards. The calibration curves were linear from 0.00467 to 3.2 μg/mL for MPA/MPAG and from 0.00467 to 0.1 μg/mL for AcMPAG. The assay was validated based on industry standards. p‐Cresol inhibited MPA glucuronidation (IC₅₀ ≈ 55 μm ) and increased MPA concentration (up to >2‐fold) at physiologically relevant substrate‐inhibitor concentrations (n = 3). Our findings suggested that fluctuations in p‐cresol concentrations might be in part responsible for the large pharmacokinetic variability observed for MPA in the clinic.     

A Novel Cesium Pentaborate with Ribbon-Type Anionic Radical

Crystallography Reports - A novel hydrated cesium hydroxypentaborate is synthesized from boric acid flux at 180°С, and its crystal structure is determined by X-ray diffraction. The...     

The Growth and Properties of Guanylurea Hydrogen Phosphite Crystal

Crystallography Reports - Aqueous solutions of guanylurea hydrogen phosphite (GUHP) have been synthesized. The temperature dependence of equilibrium GUHP concentration in water was obtained. The...     

Synthesis and Selected Reactions of 2(3)-Furoyl Phosphonates Functionalyzed at the Neighbor Position of the Furan Ring

Russian Journal of General Chemistry - Reactions of 2-and 3-furoyl chlorides having chloromethyl or butylthiomethyl group in the adjacent position of the furan ring as well as of analogous...     

Self‐assembled polyurea macromer nanodispersion and resulting hybrid polyurea‐acrylic emulsions and films

A polyurea macromer (PUM) was synthesized and dispersed in basic conditions to form self‐assembled nanoparticles (<20 nm dispersions, up to 30 wt % aq. soln.). These nanoparticles enabled surfactant‐free emulsion polymerization to form hybrid polyurea‐acrylic particles despite the absence of a measureable water‐soluble fraction. The T_g of the starting PUM material was a strong function of the PUM's extent of neutralization and hydration (varying between 100 °C and >175 °C) due to changes in hydrogen and ionic bonding. Two separate hybrid polyurea‐acrylic emulsion systems were prepared: one by direct polymerization of (meth)acrylic monomers in the presence of the nanodispersion and a second by a physical blend of PUM nanodispersion with an acrylic latex control. The direct polymerization method resulted in a hybrid emulsion particle size that developed by a mechanism resembling conventional emulsion polymerization and was unlike that described for seeded polyurethane dispersion systems. Film hardness was shown to increase with increasing coating thickness for the hybrid film prepared by direct polymerization. The resulting mechanical properties could be explained by applying mechanical models for a composite foam structure. These results were unprecedented for normal elastomer films. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1373–1388     

Self-Assembly of C3 Symmetric Rigid Macrolactams into Very Polar and Porous Trigonal Crystals

Cyclohexane and cyclotri-β-alanyl have been used as scaffolds for the design of new C₃-symmetric rings incorporating conjugated alkenes and dienes. All three C₃-symmetric lactams share the same triangular shape and their crystal system is trigonal. They all belong to the R3 space group, R3m, R3 and R3c, for the increasingly large 12-, 18- and 24-membered rigid rings, respectively. All lactams stack on top of each other, through H-bonds and van der Waals noncovalent interactions, leading to endless supramolecular cylinders and tubes. The largest member of the family leads to tubes, the central pores of which is wide enough to let water in. A common feature of all the lactams is their very large dipole, of around 9 D, according to DFT calculations. Surprisingly, all the resulting cylinders and tubes pack side by side in the crystals, with all the dipoles pointing to the same direction. As a result, all three crystals are anisotropic and appear to be the first members of a new kind of highly polar crystals.     

Separation technique based on electrophoresis,chromatography and magnetism phenomena: the migration time and peak broadening

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Pericyclic reactions in the synthesis of new 5-aryl-5,6-dihydroquinolino[2,1-b]quinazolin-12-ones

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Synthesis of Functionalized Tetrahydropyridines by SnCl4-Mediated [4+2] Cycloaddition between Donor–Acceptor Cyclobutanes and Nitriles

Cycloadditions of strained carbocycles promoted by Lewis acids are powerful methods to construct heterocyclic frameworks. In fact, the formal [3+2] cycloadditions of donor–acceptor (DA) cyclopropanes with nitriles has seen particular success in synthesis. In this work, we report on the first [4+2] cycloaddition of nitriles with DA cyclobutanes by Lewis acid activation. Tetrahydropyridine derivatives were obtained in up to 91 % yield from various aryl-activated cyclobutane diesters and aliphatic or aromatic nitriles.     

Lithium–Bromide Exchange versus Nucleophilic Addition of Schiff's base: Unprecedented Tandem Cyclisation Pathways

By exploring lithium–bromide exchange reactivity of aromatic Schiff's bases with tert-butyllithium (tBuLi), we have revealed unprecedented competitive intermolecular and intramolecular cascade annulation pathways, leading to valuable compounds, such as iso-indolinones and N-substituted anthracene derivatives. A series of reaction parameters were probed, including solvent, stoichiometry, sterics and organolithium reagent choice, in order to understand the influences that limit such ring-closing pathways. With two viable reactivity options for the organolithium on the imine; namely, nucleophilic addition or lithium–bromide exchange, a surprising competitive nature was observed, where nucleophilic addition dominated, even under cryogenic conditions. Considering the most commonly used solvents for lithium–bromide exchange, tetrahydrofuran (THF) and diethyl ether (Et₂O), contrasting reactivity outcomes were revealed with nucleophilic addition promoted in THF, while Et₂O yielded almost double the conversion of cyclic products than in THF.