Isobaric metabolite interferences and the requirement for close examination of raw data in addition to stringent chromatographic separations in liquid chromatography/tandem mass spectrometric analysis of drugs in biological matrix

In addition to matrix effects, common interferences observed in liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses can be caused by the response of drug-related metabolites to the multiple reaction monitoring (MRM) channel of a given drug, as a result of in-source reactions or decomposition of either phase I or II metabolites. However, it has been largely ignored that, for some drugs, metabolism can lead to the formation of isobaric or isomeric metabolites that exhibit the same MRM transitions as parent drugs. The present study describes two examples demonstrating that interference caused by isobaric or isomeric metabolites is a practical issue in analyzing biological samples by LC/MS/MS. In the first case, two sequential metabolic reactions, demethylation followed by oxidation of a primary alcohol moiety to a carboxylic acid, produced an isobaric metabolite that exhibits a MRM transition identical to the parent drug. Because the drug compound was rapidly metabolized in rats and completely disappeared in plasma samples, the isobaric metabolite appeared as a single peak in the total ion current (TIC) trace and could easily be quantified as the drug since it was eluted at a retention time very close to that of the drug in a 12-min LC run. In the second example, metabolism via the ring-opening of a substituted isoxazole moiety led to the formation of an isomeric product that showed an almost identical collision-induced dissociation (CID) MS spectrum as the original drug. Because two components were co-eluted, the isomeric product could be mistakenly quantified and reported by data processing software as the parent drug if the TIC trace was not carefully inspected. Nowadays, all LC/MS data are processed by computer software in a highly automated fashion, and some analysts may spend much less time to visually examine raw TIC traces than they used to do. Two examples described in this article remind us that quality data require both adequate chromatographic separations and close examination of raw data in LC/MS/MS analyses of drugs in biological matrix.     

Exploiting barrier distributions to investigate breakup effects in the fusion of 9Be+208Pb

The availability of precisely measured fusion excitation functions have allowed the determination of experimental fusion barrier distributions. This concept is utilised in ⁹Be+²⁰⁸Pb reaction, to reliably predict the expected complete fusion cross-sections. However, the measured cross-sections are found to be only 68% of those predicted. The large cross-sections observed for incomplete fusion products support the interpretation that this suppression of fusion is caused by ⁹Be breaking up into charged fragments before reaching the fusion barrier.     

The Total Synthesis of Eleutherobin: A Surprise Ending

An “sp ² –sp ³ Stille coupling” of the vinyl triflate 1 and the stannyl compound 2 is a key step toward the completion of the total synthesis of eleutherobin, a natural product exhibiting taxol-like cytotoxic activity.     

pH‐Dependent Nitrotyrosine Formation in Ribonuclease A is Enhanced in the Presence of Polyethylene Glycol (PEG)

Protein nitration can occur as a result of peroxynitrite‐mediated oxidative stress. Excess production of peroxynitrite (PN) within the cellular medium can cause oxidative damage to biomolecules. The in vitro nitration of Ribonuclease A (RNase A) results in nitrotyrosine (NT) formation with a strong dependence on the pH of the medium. In order to mimic the cellular environment in this study, PN‐mediated RNase A nitration has been carried out in a crowded medium. The degree of nitration is higher at pH 7.4 (physiological pH) compared to pH 6.0 (tumor cell pH). The extent of nitration increases significantly when PN is added to RNase A in the presence of crowding agents PEG 400 and PEG 6000. PEG has been found to stabilize PN over a prolonged period, thereby increasing the degree of nitration. NT formation in RNase A also results in a significant loss in enzymatic activity.     

Local Mechanical Behavior of Steel Exposed to Nonlinear Harmonic Oscillation

The local mechanical behavior of fatigued steel specimens was probed using nanoindentation. High-carbon steel cantilevers were exposed to nonlinear harmonic oscillation. The indentation modulus on the beam surface and plastic work during indentation decreased as a function of cycles, which was attributed to grain fragmentation and reorientation as well as the continuous reduction in inherent energy dissipation capacity of the material. X-ray diffraction, electron backscatter diffraction, and atomic force microscopy were used to characterize this microstructural evolution during early stages of the beam fatigue life, which altered 1) the local mechanical properties and 2) the global structural dynamic response. The results provide insight into fatigue damage precursors and provides a framework for connecting materials evolution with nonlinear structural dynamics.     

Radiation response behaviour of Al codoped germano-silicate SM fiber at high radiation dose

Radiation response behaviour of Ge + Al doped SM fiber fabricated by the solution doping process has been studied at room temperature with respect to 1310 nm transmission wavelength under three different dose rates of 200, 400 and 600 Rad/min to compare with that of standard Er doped as well as Ge doped SM fibers. Their radiation sensitivity has been observed with variation of dose rates, transmission wavelength along with their recovery nature. Radiation response behaviour of Al doped SM fiber is found to be slightly non-linear in nature with very low dose rate dependency. No saturation level was found upto 13 Krad cumulative dose. Thermobleaching as well as photobleaching phenomena have also been studied. Gamma irradiated Al doped preform shows an absorption peak at around 300 nm due to generation of Al (E′) defect center and gets annihilated after thermobleaching process. Gamma irradiated Al doped SM fiber shows prominent photobleaching effect on their optical attenuation with respect to the 850 nm transmission wavelength. From ESR study resonance signals for Al³⁺ related radiation-induced defect centers are not clearly observed in this study. A very weak hyperfine pattern has been observed for gamma irradiated Al doped preform sample. The high radiation sensitivity along with linear response behaviour, low recovery and almost dose rate independence behaviour of the material system of Ge + Al codoped SM core optical fiber under gamma radiation shows their potential for application as fiber optic radiation sensor in comparison to the universal standard erbium doped SM fiber.     

Syntheses,structures and electrochemistry of manganese(III) complexes derived from N,N′-o-phenylenebis(3-ethoxysalicylaldimine): Efficient catalyst for styrene epoxidation

Syntheses, characterizations, electrochemistry and catalytic properties for styrene epoxidation of three manganese(III) compounds [Mn^IIIL¹(H₂O)(MeOH)](ClO₄) (1) [Mn^IIIL¹(N₃)(H₂O)]·dmf (2) [Mn^IIIL¹(Cl)(H₂O)] (3) derived from the Schiff base compartmental ligand N,N′-o-phenylenebis(3-ethoxysalicylaldimine) (H₂L¹) are reported. The three compounds are characterized by elemental analyses, IR, mass and UV–Vis spectra and conductance values. Single crystal X-ray structures of 1 and 2 have been determined. The structures of 1 and 2 show that these are mononuclear compounds having a salen type structure. In both structures, a dinuclear species is formed by bifurcated hydrogen bonding involving coordinated water molecule. The coordination of chloride in 3 is shown by conductance measurements. The compounds have also been characterized by UV–Vis and mass spectroscopic studies. Cyclic voltammetric and square wave voltammetric studies of the three compounds reveal that these undergo Mn(III)/Mn(II) reduction reversibly with the order of the ease of reduction as 3 > 2 > 1. This order has been explained proposing the composition of active species in solution. Catalytic properties for epoxidation of styrene by all the three complexes using PhIO and NaOCl as oxidant have been studied. The order of both the styrene conversion and styrene epoxidation using the three title compounds is 3 > 1 > 2. Again, it has been observed that more efficient conversion and epoxidation take place when PhIO is used as oxidant.