Differentiating Isobaric Steroid Hormone Metabolites Using Multi-Stage Tandem Mass Spectrometry

Steroid hormones and their metabolites are currently undergoing clinical trials as potential therapeutics for traumatic brain injury (TBI). To support this work, it is necessary to develop improved procedures for differentiating isobaric species in this compound class. Equilin sulfate (E-S), estrone sulfate (E1-S), 17α-dihydroequilin sulfate (ADHE-S), and 17β-dihydroequilin sulfate (BDHE-S) are primary constituents in hormone replacement therapies, such as Premarin, which are among pharmaceuticals being investigated for TBI treatment. The latter three compounds are isomers and can be difficult to differentiate in trace analytical determinations. In this work, a systematic study of the fragmentation of ADHE-S, BDHE-S, E1-S, and E-S under different stages of higher order tandem mass spectrometry (MSⁿ) and variation of collision energy, allowed optimization of conditions for distinguishing the isomeric structures. For epimeric variants (e.g., ADHE-S versus BDHE-S; α- versus β-stereoisomerization in the C-17 position), differentiation was achieved at MS⁴ and fragmentation was demonstrated through MS⁵. Computational analysis was performed to further explore differences in the fragmentation pathways due to changes in stereochemistry.      

Comparison of impurities in charcoal sorbents found by neutron activation analysis

Neutron activation of gas samples in a reactor often requires a medium to retain sufficient amounts of the gas for analysis. Charcoal is commonly used to adsorb gas and hold it for activation; however, the amount of activated sodium in the charcoal after irradiation swamps most signals of interest. Neutron activation analysis was performed on several commonly available charcoal samples in an effort to determine the activation background. The results for several elements, including the dominant sodium element, are reported. It was found that ECN charcoal had the lowest elemental background, containing sodium at 2.65 ± 0.05 ppm, as well as trace levels of copper and tungsten.     

Palladium‐Catalyzed Construction of Quaternary Stereocenters by Enantioselective Arylation of γ‐Lactams with Aryl Chlorides and Bromides

Herein, we report the first Pd‐catalyzed enantioselective arylation of α‐substituted γ‐lactams. Two sets of conditions were developed for this transformation, allowing for the use of either aryl chlorides or bromides as electrophiles. Utilizing a highly electron‐rich dialkylphosphine ligand we have been able to construct α‐quaternary centers in good yields (up to 91 % yield) and high enantioselectivities (up to 97 % ee).     

VinaMPI: Facilitating multiple receptor high‐throughput virtual docking on high‐performance computers

The program VinaMPI has been developed to enable massively large virtual drug screens on leadership‐class computing resources, using a large number of cores to decrease the time‐to‐completion of the screen. VinaMPI is a massively parallel Message Passing Interface (MPI) program based on the multithreaded virtual docking program AutodockVina, and is used to distribute tasks while multithreading is used to speed‐up individual docking tasks. VinaMPI uses a distribution scheme in which tasks are evenly distributed to the workers based on the complexity of each task, as defined by the number of rotatable bonds in each chemical compound investigated. VinaMPI efficiently handles multiple proteins in a ligand screen, allowing for high‐throughput inverse docking that presents new opportunities for improving the efficiency of the drug discovery pipeline. VinaMPI successfully ran on 84,672 cores with a continual decrease in job completion time with increasing core count. The ratio of the number of tasks in a screening to the number of workers should be at least around 100 in order to have a good load balance and an optimal job completion time. The code is freely available and downloadable. Instructions for downloading and using the code are provided in the Supporting Information. © 2013 Wiley Periodicals, Inc.     

Ritter Reactions between Alcohols and Acetonitrile Mediated by the Conducting Polymer Poly-(3,4-ethylenedioxy Thiophene) (PEDOT)

Herein, we report new reactivity of the conducting polymer, poly-(3,4-ethylenedioxy thiophene) (PEDOT), where PEDOT mediates a Ritter reaction between alcohols and acetonitrile. The yields were variable and in most cases competitive with results obtained using sulfuric acid. Attempts at a stoichiometric reaction between benzonitrile and diphenylmethanol are also reported herein. Finally, described here are preliminary mechanistic studies that suggest PEDOT is behaving as an alcohol-selective or specific Lewis acid.

Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for full experimental and spectral details.     

Selective Preparation of 4-(Bromo or Iodo)-2,5-dimethoxybenzonitrile and 2-(Bromo or Iodo)-3,6-dimethoxybenzonitrile from 2,5-Dimethoxybenzaldehyde

By use of appropriate reactions and sequence of steps, 2,5-dimethoxybenzaldehyde can be converted either to 4-(bromo or iodo)-2,5-dimethoxybenzonitrile or 2-(bromo or iodo)-3,6-dimethoxybenzonitrile.