Unveiling the Synergistic Role of Oxygen Functional Groups in the Graphene-Mediated Oxidation of Glutathione.

This is the first report of an atomic-scale direct oxidation mechanism of the thiol group in glutathione (GSH) by epoxides on graphene oxide (GO) at room temperature. The proposed reaction mechanism is determined using a coupled experimental and computational approach; active sites for the reaction are determined through examination of GO surface chemistry changes before and after exposure to GSH, and density functional theory (DFT) calculations determine the reaction barriers for the possible GO-GSH reaction schemes. The findings build on the previously established catalytic mechanism of GSH oxidation by graphenic nanocarbon surfaces and importantly identify the direct reaction mechanism which becomes important in low-oxygen environments. Experimental results suggest epoxides as the active sites for the reaction with GSH, which we confirm using DFT calculations of reaction barriers and further identify a synergism between the adjacent epoxide and hydroxyl groups on the GO surface. The direct oxidation mechanism at specific oxygen sites offers insight into controlling GO chemical reactivity through surface chemistry manipulations. This insight is critical for furthering our understanding of GO oxidative stress pathways in cytotoxicity as well as for providing rational material design for GO applications that can leverage this reaction.

Polypharmacology of Small-Molecule Modulators of the 5-Lipoxygenase Activating Protein (FLAP) Observed via a High-throughput Lipidomics Platform.

Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.

Oxidation of formic acid on the Pt(111) surface in the gas phase.

Formic acid (HCOOH) oxidation on Pt(111) under gas-phase conditions is a benchmark heterogeneous catalysis reaction used to probe electro-catalytic HCOOH conversion in fuel cells, itself an important reaction in energy conversion. We used density functional theory (DFT) calculations to elucidate the fundamental oxidation mechanisms of HCOOH in the gas phase, determining the relative strengths of chemical interactions between HCOOH oxidation intermediates and the Pt(111) surface. We focused on investigating how water and adsorption coverage affects reaction intermediate structures and transition states. Our results show that adsorbed HCOO is a reactive intermediate in gas phase, and co-adsorbed water plays a key role in HCOOH oxidation influencing the structure of reaction intermediates and reaction barriers on Pt(111). The simulations show the preferred catalytic pathway is qualitatively dependent on surface coverage. These results provide a conceptual basis to better interpret its complicated experimental reaction kinetics.

Identification of novel inhibitors of bacterial translation elongation factors.

Bacterial elongation factor Tu (EF-Tu) and EF-Ts are interacting proteins involved in polypeptide chain elongation in protein biosynthesis. A novel scintillation proximity assay for the detection of inhibitors of EF-Tu and EF-Ts, as well as the interaction between them, was developed and used in a high-throughput screen of a chemical library. Several compounds from a variety of chemical series with inhibitory properties were identified, including certain indole dipeptides, benzimidazole amidines, 2-arylbenzimidazoles, N-substituted imidazoles, and N-substituted guanidines. The in vitro activities of these compounds were confirmed in a coupled bacterial transcription-translation assay. Several indole dipeptides were identified as inhibitors of bacterial translation, with compound 2 exhibiting a 50% inhibitory concentration of 14 microM and an MIC for S. aureus ATCC 29213 of 5.6 microg/ml. Structure-activity relationship studies around the dipeptidic indoles generated additional analogs with low micromolar MICs for both gram-negative and gram-positive bacteria. To assess the specificity of antibacterial action, these compounds were evaluated in a metabolic labeling assay with Staphylococcus aureus. Inhibition of translation, as well as limited effects on other macromolecular pathways for some of the analogs studied, indicated a possible contribution from a non-target-based antibacterial mechanism of action.