Microwave-assisted direct transformation of amines to ketones using water as an oxygen source

Retro-reductive aminations, direct transformations of amines to ketones, were catalyzed by Pd/C in water under microwave irradiation.     

C7H12(2+): a prototype hexacoordinate carbonium ion

C(7)H(12)(2+) (1), the prototype hexacoordinate carbonium dication was found to be a viable minimum at the MP2/6-31G** and MP2/cc-pVTZ levels. Structure 1 is a propeller shaped molecule resembling a complex involving a C(2+) with three ethylene molecules resulting in the formation of three two-electron, three-center (2e-3c) bonds. Isomeric structure 2 was found to be 21.8 kcal/mol more stable than structure 1. However, conversion of 1 into 2 through transition structure 3 has a barrier of 5.7 kcal/mol. Related structures 4, 5, and 8 were also located as minima for C(7)H(12)(2+). The isoelectronic boron analogue BC(6)H(12)(+) (10) was also computed to be a minimum at the same level of calculations.     

Attribution of the discrepancy between ELISA and LC-MS/MS assay results of a PEGylated scaffold protein in post-dose monkey plasma samples due to the presence of anti-drug antibodies

High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA) methods were developed for the quantification of a PEGylated scaffold protein drug in monkey plasma samples. The LC-MS/MS method was based on the extraction of the therapeutic protein with a water-miscible organic solvent and the subsequent trypsin digestion of the extract followed by the detection of a surrogate peptide. The assay was linear over a range of 10-3,000 ng/mL. The ELISA method utilized a therapeutic target-binding format in which the recombinant target antigen was used to capture the drug in the sample, followed by detection with an anti-PEG monoclonal antibody. The assay range was 30-2,000 ng/mL. A correlation study between the two methods was performed by measuring the drug concentrations in plasma samples from a single-dose pharmacokinetic (PK) study in cynomolgus monkeys following a 5-mg/kg subcutaneous administration (n = 4). In the early time points of the PK profile, the drug concentrations obtained by the LC-MS/MS method agreed very well with those obtained by the ELISA method. However, at later time points, the drug concentrations measured by the LC-MS/MS method were consistently higher than those measured by the ELISA method. The PK parameters calculated based on the concentration data showed that the two methods gave equivalent peak exposure (C(max)) at 24-48 h. However, the LC-MS/MS results exhibited about 1.53-fold higher total exposure (AUC(tot)) than the ELISA results. The discrepancy between the LC-MS/MS and ELISA results was investigated by conducting immunogenicity testing, anti-drug antibody (ADA) epitope mapping, and Western blot analysis of the drug concentrations coupled with Protein G separation. The results demonstrated the presence of ADA specific to the engineered antigen-binding region of the scaffold protein drug that interfered with the ability of the drug to bind to the target antigen used in the ELISA method. In the presence of the ADAs, the ELISA method measured only the active circulating drug (target-binding), while the LC-MS/MS method measured the total circulating drug. The work presented here indicates that the bioanalysis of protein drugs may be complicated owing to the presence of drug-binding endogenous components or ADAs in the post-dose (incurred) samples. The clear understanding of the behavior of different bioanalytical techniques vis-à-vis the potentially interfering components found in incurred samples is critical in selecting bioanalytical strategies for measuring protein drugs.     

Synthesis of conformationally constrained 5,6,7, 8-Tetrahydroimidazo[1,5-a]pyridine inhibitors of farnesyltransferase

[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.     

Validation of Monte Carlo simulation of 6 MV photon beam produced by Varian Clinac 2100 linear accelerator using BEAMnrc code and DOSXYZnrc code

The Monte Carlo model for the photon-beam output from the Varian Clinac 2100 linear accelerator was validated to compare the calculated to measured PDD and beam dose profiles The Monte Carlo calculation method is considered to be the most accurate method for dose calculation in radiotherapy. The objective of this study is to build a Monte Carlo geometry of Varian Clinac 2100 linear accelerator as realistically as possible. The Monte Carlo codes used in this work were the BEAMnrc code to simulate the photons beam and the DOSXYZnrc code to examinate the absorbed dose in the water phantom. We have calculated percentage depth dose (PDD) and beam profiles of the 6 MV photon beam for the 6 × 6 cm², 10 × 10 cm² and 15 × 15 cm² field sizes. We have used the gamma index technique for the quantitative evaluation to compare the measured and calculated distributions. Good agreement was found between calculated PDD and beam profile compared to measured data. The comparison was evaluated using the gamma index method and the criterions were 3% for dose difference and 3 mm for distance to agreement. The gamma index acceptance rate was more than 97% of both distribution comparisons PDDs and dose profiles and our results were more developed and accurate. The Varian Clinac 2100 linear accelerator was accurately modeled using Monte Carlo codes: BEAMnrc and DOSXYZnrc codes package.     

Preparation of α-Bromo- and α-Chlorocarboxylic Acids from α-Amino Acids

Diazotization of α-amino acids in 48:52 (w/w) hydrogen fluoride/pyridine along with excess of potassium halide results in the corresponding α-halocarboxylic acids in good to excellent yields (Table 1 and 2).     

Tunneling and Parity Violation in Trisulfane (HSSSH): An Almost Ideal Molecule for Detecting Parity Violation in Chiral Molecules

Measuring the parity‐violating energy difference Δ_pvE between the enantiomers of chiral molecules is a major challenge of current physical‐chemical stereochemistry. An important step towards this goal is to identify suitable molecules for such experiments by means of theory. This step has been made by calculations for the complex dynamics of tunneling and electroweak quantum chemistry of parity violation in the “classic” molecule trisulfane, HSSSH, which satisfies the relevant conditions for experiments almost ideally, as the molecule is comparatively simple and parity violation clearly dominates over tunneling in the ground state. At the same time, the barrier for stereomutation is easily overcome by the S?H infrared chromophore.