Determination of PF‐04620110, a novel inhibitor of diacylglycerol acyltransferase‐1, in rat plasma using liquid chromatography–tandem mass spectrometry and its application in pharmacokinetic studies

In this study, we developed a method for the determination of PF‐04620110 (2‐{(1r,4r)‐4‐[4‐(4‐amino‐5‐oxo‐7,8‐dihydropyrimido[5,4‐f][1,4]oxazepin‐6(5H)‐yl)phenyl]cyclohexyl}acetic acid), a novel diacylglycerol acyltransferase 1 (DGAT‐1) inhibitor, in rat plasma and validated it using liquid chromatography–tandem mass spectrometry (LC‐MS/MS). Rat plasma samples were processed following a protein precipitation method by using acetonitrile and were then injected into an LC‐MS/MS system for quantification. PF‐04620110 and imipramine (internal standard) were separated using a Hypersil Gold C₁₈ column, with a mixture of acetonitrile and 10 mm ammonium formate (90:10, v/v) as the mobile phase. The ion transitions monitored in positive‐ion mode [M + H]⁺ of multiple‐reaction monitoring were m/z 397.0 → 260.2 for PF‐04620110 and m/z 280.8 → 86.0 for imipramine. The detector response was specific and linear for PF‐04620110 at concentrations within the range 0.05–50 µg/mL and the signal‐to‐noise ratios for the samples were ≥10. The intra‐ and inter‐day precision and accuracy of the method matched the acceptance criteria for assay validation. PF‐04620110 was stable under various processing and/or handling conditions. PF‐04620110 concentrations in the rat plasma samples could be measured up to 24 h after intravenous or oral administration of PF‐04620110, suggesting that the assay is useful for pharmacokinetic studies in rats. Copyright © 2013 John Wiley & Sons, Ltd.     

Highly enantioselective synthesis of alpha-alkyl-alanines via the catalytic phase-transfer alkylation of 2-naphthyl aldimine tert-butyl ester by using O(9)-allyl-N(1)-2',3',4'-trifluorobenzylhydrocinchonidinium bromide

Systematic investigations to develop an efficient enantioselective synthetic method for alpha-alkyl-alanine by catalytic phase-transfer alkylation were performed. The alkylation of 2-naphthyl aldimine tert-butyl ester, 1E, with RbOH and O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide, 6, at -35 degrees C showed the highest enantioselectivities, up to 96% ee.     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

NMR analysis of lignins in CAD-deficient plants. Part 1. Incorporation of hydroxycinnamaldehydes and hydroxybenzaldehydes into lignins

Peroxidase/H2O2-mediated radical coupling of 4-hydroxycinnamaldehydes produces 8-O-4-, 8-5-, and 8-8-coupled dehydrodimers as has been documented earlier, as well as the 5-5-coupled dehydrodimer. The 8-5-dehydrodimer is however produced kinetically in its cyclic phenylcoumaran form at neutral pH. Synthetic polymers produced from mixtures of hydroxycinnamaldehydes and normal monolignols provide the next level of complexity. Spectral data from dimers, oligomers, and synthetic polymers have allowed a more substantive assignment of aldehyde components in lignins isolated from a CAD-deficient pine mutant and an antisense-CAD-downregulated transgenic tobacco. CAD-deficient pine lignin shows enhanced levels of the typical benzaldehyde and cinnamaldehyde end-groups, along with evidence for two types of 8-O-4-coupled coniferaldehyde units. The CAD-downregulated tobacco also has higher levels of hydroxycinnamaldehyde and hydroxybenzaldehyde (mainly syringaldehyde) incorporation, but the analogous two types of 8-O-4-coupled products are the dominant features. 8-8-Coupled units are also clearly evident. There is clear evidence for coupling of hydroxycinnamaldehydes to each other and then incorporation into the lignin, as well as for the incorporation of hydroxycinnamaldehyde monomers into the growing lignin polymer. Coniferaldehyde and sinapaldehyde (as well as vanillin and syringaldehyde) co-polymerize with the traditional monolignols into lignins and do so at enhanced levels when CAD-deficiency has an impact on the normal monolignol production. The implication is that, particularly in angiosperms, the aldehydes behave like the traditional monolignols and should probably be regarded as authentic lignin monomers in normal and CAD-deficient plants.     

pH-responsive self-duplex of (Py)A-substituted oligodeoxyadenylate in graphene oxide solution as a molecular switch

In this paper, we demonstrated a highly discriminated and reliable molecular switch based on the interaction between the self-duplex of (Py)A-substituted oligodeoxyadenylate and graphene oxide in aqueous solution. This system showed a clear on/off state through the association and dissociation of (Py)A-modified oligodeoxynucleotide with graphene oxide in manipulated pH conditions, high amplitude efficiency for at least 50 cycles, and rapid response within seconds. Our molecular switch system has high reproducibility and simple operation by using pH stimulus.     

Differential 3ω calorimeter

We have developed a new dynamic calorimeter using the differential 3ω detection method. The differential 3ω calorimeter is capable of measuring dynamic heat capacity of liquid samples. The new calorimeter consists of a Wheatstone bridge made of two identical heater/sensors, and is based on the sensitive null detection method. The balancing is done automatically at all frequencies and is independent of temperature; once a sample is placed on one heater/sensor, a third harmonic signal is produced due to the difference in the two arms of the bridge. The differential 3ω calorimeter provides enhancements over traditional dynamic methods in dynamic range (up to 30 kHz), resolution, and ease of operation.     

Supramolecular conducting microfibers from amphiphilic tetrathiafulvalene-based organogelator

An amphiphilic tetrathiafulvalene molecule can gelate a variety of organic solvents in view of multiple intermolecular interactions, especially in polar solvent with the formation of highly-ordered columnar structures. The formation of mixed-valence states shows the semiconductive behaviors with the conductivity of 10^-4 S/cm, as promising candidates for organic electronics.     

Alkoxide-Promoted Selective Hydroboration of N-Heteroarenes: Pivotal Roles of in situ Generated BH3 in the Dearomatization Process

While numerous organo(metallic)catalyst systems were documented for dearomative hydroboration of N-aromatics, alkoxide base catalysts have not been disclosed thus far. Described herein is the first example of alkoxide-catalyzed hydroboration of N-heteroaromatics including pyridines, providing a broad range of reduced N-heterocycles with high efficiency and selectivity. Mechanistic studies revealed an unprecedented counterintuitive dearomatization pathway, in which 1) pyridine-BH₃ adducts undergo a hydride attack by alkoxyborohydrides, 2) in situ generated BH₃ serves as a catalytic promoter, and 3) 1,4-dihydropyridyl borohydride is in a predominant resting state.     

Styrene‐N‐phenylacrylamide co‐polymer modified silica monolith particles with an optimized mixing ratio of monomers as a new stationary phase for the separation of peptides in high performance liquid chromatography

A stationary phase was prepared by chemical derivatization of the support particles with a layer of copolymer composed of styrene and N‐phenyl acrylamide. Silica monolith particles of ca. 2.6 µm (volume‐based average) have been prepared as the support particles by sol‐gel reaction followed by differential sedimentation. The particles were reacted with 3‐chloropropyl trimethoxysilane followed by sodium diethyldithiocarbamate to introduce an initiator moiety. Then, the copolymer layer was immobilized via reversible addition‐fragmentation transfer polymerization. The resultant phase was packed in glass‐lined stainless‐steel micro‐columns (1 x 150 mm) and evaluated for the separation of a mixture composed of five peptides (Trp‐Gly, Thr‐Tyr‐Ser, angiotensin I, isotocin and bradykinin). The effect of monomer mixing ratio (styrene versus N‐phenyl acrylamide) on the chromatographic separation efficiency of the stationary phase was examined. A number of theoretical plates (N) as high as 33 600 plates/column (224 000 plates/m, 4.46 µm plate height) was achieved using the column packed with the optimized stationary phase. The column‐to‐column reproducibility based on three columns packed with three different batches of stationary phase was found satisfactory in separation efficiency, retention factor, and asymmetry factor.