Quantitative analysis of enasidenib in dried blood spots of mouse blood using an increased‐sensitivity LC–MS/MS method: Application to a pharmacokinetic study

A simple, sensitive and rapid assay method has been developed and validated as per regulatory guidelines for the estimation of enasidenib on mouse dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive‐ion mode. The method employs liquid extraction of enasidenib from DBS disks of mouse whole blood followed by chromatographic separation using 0.2% formic acid–acetonitrile (25:75, v/v) at a flow rate of 1.0 mL/min on an Atlantis dC₁₈ column with a total run time of 2.0 min. The MS/MS ion transitions monitored were m/z 474.0 → 267.1 for enasidenib and m/z 309.2 → 251.3 for the internal standard (warfarin). The assay was linear in the range of 1.01 – 3044 ng/mL. The within‐run and between‐run precisions were in the range of 3.18 – 9.06 and 4.66 – 8.69%, respectively. Stability studies showed that enasidenib was stable on DBS cards for 1 month. This novel method has been applied to analyze the DBS samples of enasidenib obtained from a pharmacokinetic study in mice.     

Nanohoop Rotaxanes from Active Metal Template Syntheses and Their Potential in Sensing Applications

The unique optoelectronic properties and smooth, rigid pores of macrocycles with radially oriented π systems render them fascinating candidates for the design of novel mechanically interlocked molecules with new properties. Two high‐yielding strategies are used to prepare nanohoop [2]rotaxanes, which owing to the π‐rich macrocycle are highly emissive. Then, metal coordination, an intrinsic property afforded by the resulting mechanical bond, can lead to molecular shuttling as well as modulate the observed fluorescence in both organic and aqueous conditions. Inspired by these findings, a self‐immolative [2]rotaxane was then designed that self‐destructs in the presence of an analyte, eliciting a strong fluorescent turn‐on response, serving as proof‐of‐concept for a new type of molecular sensing material. More broadly, this work highlights the conceptual advantages of combining compact π‐rich macrocyclic frameworks with mechanical bonds formed via active‐template syntheses.     

Palladium‐catalysed room‐temperature Suzuki–Miyaura coupling in water extract of pomegranate ash,a bio‐derived sustainable and renewable medium

An agro waste‐derived, ‘water extract of pomegranate ash’ (WEPA), has been utilized for the first time as a renewable medium for Pd(OAc)₂‐catalysed Suzuki–Miyaura cross‐coupling at room temperature. This method offers a simple and sustainable synthesis of biaryls from aryl halides and arylboronic acids under ligand‐ and external base‐free aerobic and ambient conditions. This method has been found effective for both activated and unactivated aryl halides in the production of biaryls with moderate to nearly quantitative yields. The protocol shows high chemoselectivity over identical/similar reactive sites in aryl halides (i.e. selectivity over identical halogens or different halogens of aryl halides). This method exhibits high regioselectivity, i.e. the selective reactivity of a halogen over other identical halogens at different positions on the aromatic nucleus. Therefore, we disclose here a clean, benign, substantial chemo‐ and regioselective and highly economic alternative method for the palladium‐assisted synthesis of biaryls using an agro waste‐derived medium.     

A Sensitive HPTLC method for Estimation of Swertiamarin in Enicostemma littorale Blume,Swertia chirata (Wall) Clarke,and in formulations containing E. littorale

JPC – Journal of Planar Chromatography – Modern TLC - Swertiamarin is a secoiridoid glucoside present in members of the Gentianaceae family, including Swertia chirata (Wall) Clarke, S....     

Efficient oxidizing methods for the synthesis of oxandrolone intermediates

Mild, efficient and eco-friendly oxidation of 17alpha-methylandrostan-3beta-17beta-diol (1) has been studied with three different reagents viz. pentavalent iodine reagent 2-iodoxy benzoic acid (IBX) in DMSO at 65 degrees C, sodium hypochlorite and H2O2/Na2WO4 under phase transfer conditions to give 17beta-hydroxy-17alpha-methylandrostan-3-one (mestanolone 2), a drug intermediate as oxidized product. The H2O2/Na2WO4/PTC gave mestanolone in high yield and purity whereas sodium hypochlorite/PTC system yielded some chlorinated material along with the mestanolone. However, 1 with 2.5 equivalent of IBX gave 17beta-hydroxy-17alpha-methyl-Delta1-androsten-3-one (3) under the similar reaction conditions in good yield and single step reaction.     

2,4,5-Tribromo-1H-imidazole in the egg masses of three muricid molluscs

From analysis by gas chromatography/mass spectrometry (GC/MS), the presence of either 2,4,5-tribromo-1H-imidazole (1) or 3,4,5-tribromo-1H-pyrazole (2) was tentatively identified in lipophilic extracts from the egg masses of three muricid molluscs. Synthesis of these compounds, followed by comparison of the GC retention times and fragmentation patterns from electron impact MS, with those of the natural products, indicated that it was 2,4,5-tribromo-1H-imidazole rather than the pyrazole. This imidazole is likely to be responsible for some of the antimicrobial activity observed in the egg extracts. This is the first report of this compound from a natural source.     

Synthesis and antispasmodic activity evaluation of bis-(papaverine) analogues

A new series of N-substituted bis-(tetrahydropapaverine) ring systems have been synthesised in expectation of better antispasmodic activity in comparison with papaverine. The synthesis of the targeted heterocycles is described along with a discussion of their structure activity relationship. The general synthetic methods of bis-(tetrahydropapaverine) analogues involve tetrahydropapaverine, various piperazines, diisocyanates and diisothiocyanates as starting materials. Pharmacological evaluation involves the in vitro antispasmodic activity on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, N,N'-bis-[2-carbamoyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl]piperazine (22), was found to be the most potent muscle relaxant (IC(50): 0.31 microM).     

Nitric oxide reactivity of copper(II) complexes of bidentate amine ligands: effect of chelate ring size on the stability of a [Cu(II)-NO] intermediate

Three copper(II) complexes, 1, 2, and 3 with L(1), L(2) and L(3) [L(1) = 2-(2-aminoethyl)-pyridine; L(2) = 2-(N-ethyl-2-aminoethyl)-pyridine; L(3) = 3,3'-iminobis(N,N-dimethylpropylamine)], respectively, were synthesized and characterized. Addition of nitric oxide gas to the degassed acetonitrile solution of the complexes were found to result in the reduction of the copper(II) center to copper(I). In cases of complexes 1 and 2, the formation of the [Cu(II)-NO] intermediate prior to the reduction of Cu(II) was evidenced by UV-visible, solution FT-IR and X-band EPR spectroscopic studies. However, for complex 3, the formation of [Cu(II)-NO] has not been observed. DFT calculations on the [Cu(II)-NO] intermediate generated from complex 1 suggest a distorted square pyramidal geometry with the NO ligand coordinated to the Cu(II) center at an equatorial site in a bent geometry. In the case of complex 1, the reduction of the copper(II) center by nitric oxide afforded ligand transformation through diazotization at the primary amine site in acetonitrile solution; whereas, in an acetonitrile-water mixture, it resulted in 2-(pyridine-2-yl)ethanol. On the other hand, in cases of complexes 2 and 3, it was found to yield N-nitrosation at the secondary amine site in the ligand frameworks. The final organic products, in each case, were isolated and characterized by various spectroscopic studies.     

Pd-catalyzed amination of 6-halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one

6-Halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one derivatives have been synthesized and utilized for amination reactions with aryl, heteroaryl and alkyl amines. Optimization of reaction conditions with different catalysts, ligands, bases, and solvents was conducted. The combination of Pd₂(dba)₃ with DavePhos (L3) proved to be best for these conversions in the presence of NaO^tBu in 1,4-dioxane at 100 °C. The relative reactivities of 6-bromo and 6-chloro-2,3-disubstitued quinazolinones with p-toluidine were conducted and as anticipated the 6-bromo analogue was totally consumed and 6-chloro derivative was completely unreactive.     

Development and validation of liquid chromatography-mass spectrometric method for simultaneous determination of moxifloxacin and ketorolac in rat plasma: application to pharmacokinetic study

A highly sensitive, selective and rapid liquid chromatography–electrospray ionization mass spectrometry (LC‐MS) method has been developed and validated for simultaneous determination of moxifloxacin (MFX) and ketorolac (KTC) in rat plasma. Gemifloxacin (GFX) was used as an internal standard (IS). A simple protein precipitation method was used for the extraction of analytes from rat plasma. Effective chromatographic separation of MFX, KTC and GFX was achieved on a Kromasil C₁₈ column (100 × 4.6 mm, 5 µm) using a mobile phase consisting of acetonitrile–10 mm ammonium acetate (pH 2.5)–0.1% formic acid (50:25:25) in an isocratic elution, followed by detection with positive ion electrospray ionization mass spectrometry using target ions of [M + H]⁺ at m/z 402 for MFX, m/z 256 for KTC and m/z 390 for GFX in selective ion recording mode. The method was validated over the calibration range of 5–100 ng/mL for MFX and 10–6000 ng/mL for KTC. The method demonstrated good performances in terms of intra‐ and inter‐day precision (0.97–5.33%) and accuracy (93.91–101.58%) for both MFX and KTC, including lower and upper limits of quantification. The recoveries from spiked control samples were >75% for MFX and >79% for KTC. The matrix effect was found to be negligible and the stability data were within acceptable limits. Further, the method was also successfully applied to a single‐dose pharmacokinetic study in rats. This method can be extended to measure plasma concentrations of both drugs in human to understand drug interaction and adverse effects. Copyright © 2012 John Wiley & Sons, Ltd.