A perillyl alcohol-conjugated analog of 3-bromopyruvate without cellular uptake dependency on monocarboxylate transporter 1 and with activity in 3-BP-resistant tumor cells.

The anticancer agent 3-bromopyruvate (3-BP) is viewed as a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on cellular drug import through transmembrane monocarboxylate transporter 1 (MCT-1), which restricts its anticancer potential to MCT-1-positive tumor cells. We created and characterized an MCT-1-independent analog of 3-BP, called NEO218.

Tandem analysis of transcriptome and proteome changes after a single dose of corticosteroid: a systems approach to liver function in pharmacogenomics.

Corticosteroids (CS) such as methylprednisolone (MPL) affect almost all liver functions through multiple mechanisms of action, and long-term use results in dysregulation causing diverse side effects. The complexity of involved molecular mechanisms necessitates a systems approach. Integration of information from the transcriptomic and proteomic responses has potential to provide deeper insights into CS actions.

Kinetics of precursor labeling in stable isotope labeling in cell cultures (SILAC) experiments.

Recent advances in mass spectrometry have enabled proteome-wide analyses of cellular protein turnover. These studies have been greatly propelled by the development of stable isotope labeling in cell cultures (SILAC), a set of standardized protocols, reagents aimed at quantifying the incorporation of (15)N/(13)C labeled amino acids into proteins. In dynamic SILAC experiments, the degree of isotope incorporation in proteins is measured over time and used to determine turnover kinetics.

Highly multiplexed and reproducible ion-current-based strategy for large-scale quantitative proteomics and the application to protein expression dynamics induced by methylprednisolone in 60 rats.

A proteome-level time-series study of drug effects (i.e., pharmacodynamics) is critical for understanding mechanisms of action and systems pharmacology, but is challenging, because of the requirement of a proteomics method for reliable quantification of many biological samples.

Effects of calibration approaches on the accuracy for LC-MS targeted quantification of therapeutic protein.

LC-MS provides a promising alternative to ligand-binding assays for quantification of therapeutic proteins and biomarkers. As LC-MS methodology is based on the analysis of proteolytic peptides, calibration approaches utilizing various calibrators and internal standards (I.S.

Electrocatalytic oxidation of hydrogen peroxide on a platinum electrode in the imitation of oxidative drug metabolism of lidocaine.

Electrochemistry in combination with mass spectrometry has shown promise as a versatile technique not only in the analytical assessment of oxidative drug metabolism, but also for small-scale synthesis of drug metabolites. However, electrochemistry is generally limited to reactions initiated by direct electron transfer. In the case of substituted-aromatic compounds, oxidation proceeds through a Wheland-type intermediate where resonance stabilization of the positive charge determines the regioselectivity of the anodic substitution reaction, and hence limits the extent of generating drug metabolites in comparison with in vivo oxygen insertion reactions.

Electrochemical oxidation by square-wave potential pulses in the imitation of phenacetin to acetaminophen biotransformation.

Electrochemistry in combination with mass spectrometry is emerging as a versatile analytical technique in the imitation of oxidative drug metabolism during the early stages of drug discovery and development. Here, we present electrochemical O-dealkylation of phenacetin to acetaminophen by square-wave potential pulses consisting of consecutive sub-second oxidation and reduction steps. This O-dealkylation could not be achieved by oxidation at constant potential or longer potential pulses because of the fast hydrolysis of the reactive intermediates.

Electrochemical oxidation by square-wave potential pulses in the imitation of oxidative drug metabolism.

Electrochemistry combined with mass spectrometry (EC-MS) is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Here, we present the benefits of electrochemical oxidation by square-wave potential pulses for the oxidation of lidocaine, a test drug compound, on a platinum electrode. Lidocaine was oxidized at constant potential and by square-wave potential pulses with different cycle times, and the reaction products were analyzed by liquid chromatography-mass spectrometry [LC-MS(/MS)].

Electrochemistry in the mimicry of oxidative drug metabolism by cytochrome P450s.

Prediction of oxidative drug metabolism at the early stages of drug discovery and development requires fast and accurate analytical techniques to mimic the in vivo oxidation reactions by cytochrome P450s (CYP). Direct electrochemical oxidation combined with mass spectrometry, although limited to the oxidation reactions initiated by charge transfer, has shown promise in the mimicry of certain CYP-mediated metabolic reactions. The electrochemical approach may further be utilized in an automated manner in microfluidics devices facilitating fast screening of oxidative drug metabolism.

Lidocaine oxidation by electrogenerated reactive oxygen species in the light of oxidative drug metabolism.

The study of oxidative drug metabolism by Cytochrome P450s (P450) is important in the earlier stages of drug development. For this purpose, automated analytical techniques are needed for fast and accurate estimation of oxidative drug metabolism. Previous studies have shown that electrochemistry in combination with mass spectrometry is a versatile analytical technique to generate drug metabolites that result from direct electron transfer.