Biotransformation of musk xylene in trout haemoglobin: dose–response and toxicokinetics of musk xylene metabolites haemoglobin adducts by gas chromatography-mass spectrometry

Musk xylene (MX) is frequently used as a fragrance in commercial toiletries. Biotransformation of MX into 4-amino-MX (4-AMX) and 2-amino-MX (2-AMX) metabolites in rainbow trout haemoglobin (Hb) has been described. The dose–response relationship and toxicokinetics of the metabolites as adducts in the Hb were determined by gas chromatography (GC)–electron capture negative chemical ionization (NCI)–mass spectrometry (MS), and GC–electron ionization (EI)–MS/MS, using selected ion monitoring (SIM). The trout were subjected to a single exposure of 0.010, 0.030, 0.10, and/or 0.30?mg?MX/g of fish. Hb samples were collected from exposed and control fish, and analysed subsequent to exposure at intervals of 24, 72, and 168?h. Alkaline hydrolysis released 4-AMX and 2-AMX metabolites from the Hb, and the solutes were extracted into n-hexane. The extracts were preconcentrated and analysed. The presence of the metabolites in the Hb extracts was confirmed based on agreement of similar mass spectral features from NCI/MS and EI-MS/MS spectra, and retention times of the metabolites with standards. The NCI/MS results were used for dose–response and toxicokinetics measurements. For dose–response, the concentrations of adducts of the metabolites increased with dosage, and a maximum adduct formation was observed at 0.10?mg?g^?1, beyond which it decreased. The average concentrations of 4-AMX and 2-AMX at a dosage of 0.10?mg?g^?1 were 700 and 7.4?ng?g^?1, respectively. For toxicokinetics, the concentration of the metabolites in the Hb reached a maximum in the 3 day sample after administration of MX. Further elimination of the metabolites exhibited kinetics with a half-life estimated to be 1–2 days, assuming first-order kinetics. Quantitations were made based on an internal standard and a calibration plot. In control samples, non-hydrolysed Hb, and reagent blank extracts, the metabolites were not detected. The limits of detection for 4-AMX and 2-AMX in the Hb were approximately 1.7 and 1.4?µg?L^?1, respectively, based on a signal-to-noise ratio of 3 with NCI/MS.     

Directed Design of a AuI Complex with a Reduced Mesoionic Carbene Radical Ligand: Insights from 1,2,3-Triazolylidene Selenium Adducts and Extensive Electrochemical Investigations

Carbene-based radicals are important for both fundamental and applied chemical research. Herein, extensive electrochemical investigations of nine different 1,2,3-triazolylidene selenium adducts are reported. It is found that the half-wave potentials of the first reduction of the selones correlate with their calculated LUMO levels and the LUMO levels of the corresponding triazolylidene-based mesoionic carbenes (MICs). Furthermore, unexpected quasi-reversibility of the reduction of two triazoline selones, exhibiting comparable reduction potentials, was discovered. Through UV/Vis/NIR and EPR spectroelectrochemical investigations supported by DFT calculations, the radical anion was unambiguously assigned to be triazoline centered. This electrochemical behavior was transferred to a triazolylidene-type MIC-gold phenyl complex resulting in a MIC-radical coordinated Au^I species. Apart from UV-Vis-NIR and EPR spectroelectrochemical investigations of the reduction, the reduced gold-coordinated MIC radical complex was also formed in situ in the bulk through chemical reduction. This is the first report of a monodentate triazolylidene-based MIC ligand that can be reduced to its anion radical in a metal complex. The results presented here provide design principles for stabilizing radicals based on MICs.     

How Aromatic Fluorination Exchanges the Interaction Role of Pyridine with Carbonyl Compounds: The Formaldehyde Adduct

The rotational spectrum of the weakly bound complex pentafluoropyridine⋅⋅⋅formaldehyde has been investigated using Fourier transform microwave spectroscopy. From the analysis of the rotational parameters of the parent species and of the ¹³C and ¹⁵N isotopologues, the structural arrangement of the adduct has been unambiguously established. The full ring fluorination of pyridine has a dramatic effect on its binding properties: It alters the electron density distribution at the π-cloud of pyridine creating a π-hole and changing its electron donor-acceptor capabilities. In the complex, formaldehyde lies above the aromatic ring with one of the oxygen lone pairs, as conventionally envisaged, pointing toward its centre. This lone pair⋅⋅⋅π-hole interaction, reinforced by a weak C−H⋅⋅⋅N interaction, indicates an exchange of the electron-acceptor roles of both molecules when compared to the pyridine⋅⋅⋅formaldehyde adduct. Tunnelling doublets due to the internal rotation of formaldehyde have also been observed and analysed leading to a discussion on the competition between lone pair⋅⋅⋅π-hole and π⋅⋅⋅π stacking interactions.     

Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

Platinum–acridine hybrid agents show low‐nanomolar potency in chemoresistant non‐small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7‐Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent ( P1–B1 ) that maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models, while showing improved tolerability in mice by 32‐fold compared to the parent platinum–acridine ( P1–A1 ). The distribution and DNA/RNA adduct levels produced by the acridine‐ and benz[c]acridine‐based analogues in NCI‐H460 cells (confocal microscopy, ICP‐MS), and their ability to bind G‐quadruplex forming DNA sequences (CD spectroscopy, HR‐ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target‐selective hybrid agent than P1–A1 .     

Controlled Generation of 9-Boratriptycene by Lewis Adduct Dissociation: Accessing a Non-Planar Triarylborane

A highly bent triarylborane, 9-boratriptycene, was generated in solution by selective protodeboronation of the corresponding tetra-aryl boron ate complex with the strong Brønsted acid HNTf₂. The iptycene core confers enhanced Lewis acidity to 9-boratriptycene, making it unique in terms of structure and reactivity. We studied the stereoelectronic properties of 9-boratriptycene by quantifying its association with small N- and O-centered Lewis bases, as well as with sterically hindered phosphines. The resultant Lewis adducts exhibited unique structural, spectroscopic, and photophysical properties. Beyond the high pyramidalization of the 9-boratriptycene scaffold and its low reorganization energy upon Lewis base coordination, quantum chemical calculations revealed that the absence of π donation from the triptycene aryl rings to the boron vacant p_z orbital is one of the main reasons for its high Lewis acidity.     

Pulse radiolysis studies of 2‐ and 3‐hydroxybenzyl alcohols: inhibition of dehydration of ·OH‐(hydroxybenzyl alcohols) adducts by H2PO4− ions

Reactions of ·OH/O ^.? radicals and H‐atoms as well as specific oxidants such as Cl₂^.? and N₃· radicals have been studied with 2‐ and 3‐hydroxybenzyl alcohols (2‐ and 3‐HBA) at various pH using pulse radiolysis technique. At pH 6.8, ·OH radicals were found to react quite fast with both the HBAs (k = 7.8 × 10⁹ dm³ mol^?1 s^?1 with 2‐HBA and 2 × 10⁹ dm³ mol^?1 s^?1 with 3‐HBA) mainly by adduct formation and to a minor extent by H‐abstraction from ? CH₂OH groups. ·OH‐(HBA) adduct were found to undergo decay to give phenoxyl type radicals in a pH dependent way and it was also very much dependent on buffer‐ion concentrations. It was seen that ·OH‐(2‐HBA) and ·OH‐(3‐HBA) adducts react with HPO₄^2? ions (k = 2.1 × 10⁷ and 2.8 × 10⁷ dm³ mol^?1 s^?1 at pH 6.8, respectively) giving the phenoxyl type radicals of HBAs. At the same time, this reaction is very much hindered in the presence of H₂PO ions indicating the role of phosphate ion concentration in determining the reaction pathway of ·OH adduct decay to final stable product. In the acidic region adducts were found to react with H⁺ ions. At pH 1, reaction of ·OH radicals with HBAs gave exclusively phenoxyl type radicals. Proportion of the reducing radicals formed by H‐abstraction pathway in ·OH/O ^.? reactions with HBAs was determined following electron transfer to methyl viologen. H‐atom abstraction is the major pathway in O ^.? reaction with HBAs compared to ·OH radical reaction. H‐atom reaction with 2‐ and 3‐HBA gave transient species which were found to transfer electron to methyl viologen quantitatively. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of multi‐functionalized carbonyl compounds by palladium–catalysed γ‐substitution of MBH adducts with activated amides

Catalytic allylic γ‐substitution with Morita‐Baylis‐Hillman (MBH) adducts for creating a new family of unsymmetrical dicarbonyl compounds was presented in this work, in which a variety of allylated amide products were achieved in good yields and high regioselectivity with excellent linear‐to‐branched ratios. Especially, it was found that the Pd/HZNU‐Phos complex exhibited remarkably high activity (with a TON up to 16800) in this transformation between dicarbonyl amides and MBH adducts. In addition, the possibly multisite interaction between multifunctional Pd/HZNU‐Phos catalyst system and substrates might responsible for its exceptionally high efficiency in this reaction.     

An improved LC–MS/MS method for determination of docetaxel and its application to population pharmacokinetic study in Chinese cancer patients

Because of its unpredictable side effects and efficacy, the anticancer drug docetaxel (DTX) requires improved characterisation of its pharmacokinetic profiles through population pharmacokinetic studies. A sensitive and rugged LC–MS/MS method for the detection of DTX in human plasma was developed and optimised using paclitaxel as an internal standard (IS). The plasma samples underwent rapid extraction using hybrid solid-phase extraction-protein precipitation. The analyte and IS were separated with an isocratic system on a Zorbax Eclipse Plus C₁₈ column using water containing 0.05% acetic acid along with 20 μM of sodium acetate and methanol (30/70, v/v) as the mobile phase. Quantification was performed using a triple quadrupole mass spectrometer through multiple reaction monitoring in positive mode, using the m/z 830.3 → 548.8 and m/z 876.3 → 307.7 transitions for DTX and paclitaxel, respectively. The range of the calibration curve was 1–500 ng/mL for DTX, and the linear correlation coefficient was >0.99. The accuracies ranged from −4.6 to 4.2%, and the precision was no higher than 7.0% for the analytes. No significant matrix effect was observed. Both DTX and the IS showed considerable recovery. This method was finally applied to the establishment of a population pharmacokinetic model to optimise the clinical use of DTX.     

Design,synthesis, characterization,and biological evaluation of pyrido[1,2-a]pyrimidinone coumarins as promising anti-inflammatory agents

Pursuing our recent interest regarding antimicrobial and anti-inflammatory activities of coumarin derivatives, we have synthesized a series of coumarin-linked pyridopyrimidinones by using Baylis Hillman adduct in aqueous condition with high purity. Pyrido[1,2-a]pyrimidin-2-ones are important class of heterocyclic compounds because of their use in medicinal and agro chemistry as active agents. All these newly synthesized compounds were evaluated for their antimicrobial and anti-inflammatory activity. Coumarin pyridopyrimidinones showed excellent anti-inflammatory activity against both MMP-2 and MMP-9 gelatinase zymography, whereas considerable good activity against Gram-positive and Gram-negative bacterial strains; however, antifungal activity observed in these series is more or less inactive. The active compounds of these series would be promising structural templates for the development of novel and more efficient anti-inflammatory agent.