A sensitive LC‐MS/MS method for the quantification of febuxostat in human plasma and its pharmacokinetic application

An improved, simple and highly sensitive LC‐MS/MS method has been developed and validated for quantification of febuxostat with 100 μL human plasma using febuxostat‐d₇ as an internal standard (IS) according to regulatory guidelines. The analyte and IS were extracted from human plasma via liquid–liquid extraction using diethyl ether. The chromatographic separation was achieved on a Zorbax C₁₈ column using a mixture of acetonitrile and 5 mm ammonium formate (60:40, v/v) as the mobile phase at a flow rate of 0.5 mL/min. The total run time was 5.0 min and the elution of febuxostat and IS occurred at 1.0 and 1.5 min, respectively. A linear response function was established for the range of concentrations 1–6000 ng/mL (r > 0.99). The precursor to product ion transitions monitored for febuxostat and IS were m/z 317.1 → 261.1 and 324.2 → 262.1, respectively. The intra‐ and inter‐day precisions (%RSD) were within 1.29–9.19 and 2.85–7.69%, respectively. The proposed method was successfully applied to pharmacokinetic studies in humans. Copyright © 2013 John Wiley & Sons, Ltd.     

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

The aim of the present study was to evaluate the contribution of metabolites to drug–drug interaction and drug–herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α‐hydroxy metoprolol (HM), O‐desmethyl metoprolol (ODM) and N‐desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration–time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4‐catalyzed midazolam metabolism and CYP2D6‐catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug–drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.     

Cetyltrimethylammonium Bromide as an Efficient Catalyst for Regioselective Bromination of Alkoxy Naphthalenes with Trimethyl Benzyl Ammonium Tribromide: Synthetic and Kinetic Approach

Bromination of 2‐alkoxynaphthalene (2‐ANP) and its derivatives with trimethyl benzyl ammonium tribromide (TMBATB) did not proceed smoothly even under reflux conditions. But the addition of microconcentrations of cetyltrimethyl ammonium bromide (CTAB) to the reaction afforded dramatic rate accelerations as well as good‐to‐excellent yield of the products ranging from 70% to 90%. Reactions underwent regioselective monobromination at 1‐position of 2‐alkoxynaphthalene. The rate of bromination has been followed conductometrically. The reaction kinetics indicated first‐order kinetics in [2‐ANP] as well as in [TMBATB]. Kinetic results in the presence of CTAB were explained on the basis of the Raghavan–Srinivasan model as applied to micelle‐mediated bimolecular reactions.     

Two-Photon-Induced CO-Releasing Molecules as Molecular Logic Systems in Solution,Polymers, and Cells

Phototherapeutic applications of carbon monoxide (CO)-releasing molecules are limited because they require harmful UV and blue light for activation. We describe two-photon excitation with NIR light (800 nm)-induced CO-release from two Mn^I tricarbonyl complexes bearing 1,8-naphthalimide units ( 1 , 2 ). Complex 2 behaves as a logic OR gate in solution, nonwovens, and in HeLa cells. CO release, indicated by fluorescence enhancement, was detected in solution, nonwoven, and HeLa cells by single- (405 nm) and two-photon (800 nm) excitation. The photophysical properties of 1 and 2 have been measured and supported by DFT and TDDFT quantum chemical calculations. Both photoCORMs are stable in the dark in solution and noncytotoxic, leading to promising applications as phototherapeutics with NIR light.     

Hydrogen Peroxide/Boric Acid: An Efficient System for Oxidation of Aromatic Aldehydes and Ketones to Phenols

Hydrogen peroxide activated by boric acid in the presence of sulfuric acid has been shown to be an efficient oxidizing system for direct conversion of aromatic aldehydes and ketones to phenols.     

Synthesis and mesomorphic properties of banana-shaped compounds derived from 2,7-dihydroxynaphthalene

Thirty eight compounds composed of achiral banana-shaped molecules belonging to three new homologous series have been synthesized and their mesomorphic properties investigated. The mesophases have been characterized using a combination of polarized light microscopy, differential scanning calorimetry, miscibility methods and X-ray diffraction measurements. All the compounds reported exhibit mesomorphic properties. Most of the homologues in the three series show B₁ and B₂ phases and the transition temperatures of these are lower in the fluoro substituted compounds. Some of the lower homologues of the fluoro substituted derivatives also show the nematic phase.     

A convergent approach for the total synthesis of the α-glucosidase inhibitor (−)-panaxjapyne-C

The stereoselective total synthesis of (?)-panaxjapyne-C was accomplished in a convergent fashion. The synthesis utilizes the readily available enantiomers l-(+)-diethyltartrate and d-(?)-diethyltartrate and involves a Cadiot–Chodkiewicz coupling reaction, and an Ohira–Bestmann reaction as the key steps.     

Total synthesis of the 2,6-disubstituted piperidine alkaloid (−)-andrachcinidine

The total synthesis of the 2,6-disubstituted piperidine alkaloid (?)-andrachcinidine is reported using Keck’s asymmetric allylation, Sharpless epoxidation, nucleophilic substitution, and intramolecular aza-Michael addition as the key steps.