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Low-energy collision-induced dissociation tandem mass spectrometry of 7-acetonyloxycoumarins
Abstract
Coumarins are naturally occurring, oxygen-containing heterocycles with considerable pharmaceutical potential. For structural elucidation of natural or synthetic coumarins, tandem mass spectrometry (MS(n) ) represents an essential tool. In this study, fragmentation characteristics of twenty-two 7-acetonyloxycoumarins, having promising anti-inflammatory properties, were investigated with low-energy collision-induced dissociation (CID).
Accurate mass measurements were performed on a 12-T Fourier transform ion cyclotron resonance (FT-ICR) instrument. Most CID-MS(n) measurements were performed on a quadrupole ion trap (QIT) instrument, except some additional CID-MS(2) measurements performed on the FT-ICR instrument for further confirmation of some fragment ions. Positive-ion electrospray ionization (ESI) was employed throughout. Density functional theory (DFT) calculations (B3LYP) were carried out to analyze putative ion structures/fragmentation channels.
The most favourable dissociation channel for [M + H](+) ions of 7-acetonyloxycoumarins was the elimination of a C3 H5 O(●) radical (57 Da) from the 7-acetonyloxy group via homolytic bond cleavage. The resulting phenolic radical ion was the primary fragment ion for the most compounds studied. Losses of even-electron neutrals, C3 H4 O and C3 H6 O (56 and 58 Da), were also observed. These primary eliminations were accompanied with other characteristic neutral losses from the coumarin skeleton, including H2 O, CO, CO2 , and C2 H2 O (ketene). In addition, propene (C3 H6 ) loss was also observed for 4-propyl or 3-ethyl-4-methyl-substituted compounds.
The studied coumarins showed interesting characteristics in low-energy CID due to the presence of a 7-acetonyloxy group, leading to both even- and odd-electron product ions. The main dissociation channels observed for each compound were highly dependent on the substituents in the benzopyranone ring. The present results will advance our knowledge on the dissociation characteristics of both synthetic and natural coumarins. Copyright © 2013 John Wiley & Sons, Ltd.
... The analysis of glutathione conjugates formed in the incubation of 7-methylcoumarin was performed using the same system, but the initial mobile phase was 95% A (0.1% formic acid in water) and 5% B (acetonitrile), then B was increased linearly to 80% in 8 min. The identification of coumarin derivative metabolites was based on MS/MS fragmentation studies by Concannon et al. (2000), Morreel et al. (2010) and Timonen et al. (2013). ...
1. Information about the metabolism of compounds is essential in drug discovery and development, risk assessment of chemicals and further development of predictive methods. 2. In vitro and in silico methods were applied to evaluate the metabolic and inhibitory properties of 6-methylcoumarin, 7-methylcoumarin and 7-formylcoumarin with human CYP2A6, mouse CYP2A5 and pig CYP2A19. 3. 6-Methylcoumarin was oxidized to fluorescent 7-hydroxy-6-methylcoumarin by CYP2A6 (Km: 0.64-0.91 µM; Vmax: 0.81-0.89 min(-1)) and by CYP2A5 and CYP2A19. The reaction was almost completely inhibited at 10 µM 7-methylcoumarin in liver microsomes of human and mouse, but in pig only 40% inhibition was obtained with the anti-CYP2A5 antibody or with methoxsalen and pilocarpine. 7-Methylcoumarin was a mechanism-based inhibitor for CYP2A6, but not for the mouse and pig enzymes. 7-Formylcoumarin was a mechanism-based inhibitor for CYP2As of all species. 4. Docking and molecular dynamics simulations of 6-methylcoumarin and 7-methylcoumarin in the active sites of CYP2A6 and CYP2A5 demonstrated a favorable orientation of the 7-position of 6-methylcoumarin towards the heme moiety. Several orientations of 7-methylcoumarin were possible in CYP2A6 and CYP2A5. 5. These results indicate that the active site of CYP2A6 has unique interaction properties for ligands and differs in this respect from CYP2A5 and CYP2A19.
... The analysis of glutathione conjugates formed in the incubation of 7-methylcoumarin was performed using the same system, but the initial mobile phase was 95% A (0.1% formic acid in water) and 5% B (acetonitrile), then B was increased linearly to 80% in 8 min. The identification of coumarin derivative metabolites was based on MS/MS fragmentation studies by Concannon et al. (2000), Morreel et al. (2010) and Timonen et al. (2013). ...
Abstract 1. UDP-glucuronosyltransferases (UGTs) are versatile and important conjugation enzymes in the metabolism of drugs and other xenobiotics. 2. We have developed a convenient quantitative multi-well plate assay to measure the glucuronidation rate of 7-hydroxy-4-trifluoromethylcoumarin (HFC) for several UGTs. 3. We have used this method to screen 11 recombinant human UGTs for HFC glucuronidation activity and studied the reaction kinetics with the most active enzymes. We have also examined the HFC glucuronidation activity of liver microsomes from human, pig, rabbit and rat. 4. At a substrate concentration of 20 µM, the most active HFC glucuronidation catalysts were UGT1A10 followed by UGT1A6 >UGT1A7 >UGT2A1, whereas at 300 µM UGT1A6 was about 10 times better catalyst than the other recombinant UGTs. The activities of UGTs 1A3, 1A8, 1A9, 2B4 and 2B7 were low, whereas UGT1A1 and UGT2B17 exhibited no HFC glucuronidation activity. UGT1A6 exhibited a significantly higher Vmax and Km values toward both HFC and UDP-glucuronic acid than the other UGTs. 5. Human, pig and rabbit, but not rat liver microsomes, catalyzed HFC glucuronidation at high rates. 6. This new method is particularly suitable for fast activity screenings of UGTs 1A6, 1A7, 1A10 and 2A1 and HFC glucuronidation activity determination from various samples.
A series of coumarins were analyzed using electrospray ionization quadrupole time-of-flight tandem mass spectrometry in the positive-ion mode. Unexpected hydrated ions ([M + H2O + Na]+) was observed upon collision-induced dissociation of the sodiated ions ([M + Na]+) of eight coumarins. Several factors which affected relative abundance of [M + H2O + Na]+ ions such as collision energy, concentration and solvent were investigated. None of them have effect on the relative abundance of [M + H2O + Na]+. However, the peak of hydrated ions was not detected in the further collision-induced dissociation of protonated ions of coumarins. Apigenin and Quercetin sharing similar benzopyrone structural unit with coumarins are selected for tandem mass spectrometry analysis. There were no hydrated ions in their tandem mass spectrometry spectra of the precursor [M + Na]+ ions. Thus, both coumarins and sodium were necessary for the formation of [M + H2O + Na]+. Together with the result that hydrated ions are not formed by hydrolysis reactions, a six-membered ring structure which involves with the formation of [M + H2O + Na]+ was presented. And D-labeling experiment indicates that the H2O molecule did not come from solvent.
RationaleSynthetic and natural coumarin derivatives possess a wide range of biological activities. Fragmentation pathway studies are important in identifying both naturally occurring coumarins and synthetic coumarins with novel structures and properties.Methods
The fragmentation pathways of eleven coumarin derivatives are investigated by electrospray ionization (ESI) ion-trap mass spectrometry (ESI-ITMSn) and ESI quadrupole time-of-flight mass spectrometry (QTOFMS) in positive mode. Compounds 1–9 in this study were newly synthesized in our laboratory. Compounds 10 and 11 were isolated from the root of Zanthoxylum armatum.ResultsThe major fragmentation pathways for 11 coumarin derivatives are greatly affected by the heterocyclic ring structures and the side-chain substituents. Typical losses of small neutral molecules, such as CH3CH2OH, CH2=CH2, CO, and H2O, are observed for compounds 1–5. Compounds 6–9 share similar fragmentation pathways through losses of CO, aromatic rings, and the coumarin skeleton. The main product ions at m/z 205, 219, and 220 observed for compounds 10 and 11 are produced by the loss of C5H12O2, C4H10O2, and the C4H9O2 radical, respectively.Conclusions
The fragmentation pathways of 11 coumarin derivatives are elucidated based on ITMSn and QTOFMS spectral data. Differences in the structures of the heterocyclic rings and side-chain substituents strongly affect the fragmentation pathways of the coumarins. The present results will facilitate further research into the fragmentation pathways and structural characterization of these classes of compounds with diverse structures. Copyright © 2015 John Wiley & Sons, Ltd.
The mass spectra of some naturally occurring and synthetic α- and γ-pyrones, benzofurans, and 2,2-dimethylchromenes have been determined. Under electron impact compounds derived from coumarin lose oxygen atoms as CO, usually forming a stable benzofuran ion. 2,2-Dimethylchromenes lose a methyl radical to give a stable benzopyrylium ion, while the most prominent fission of flavanoid compounds occurs by breaking both bonds β to the A ring.
5-Phenyl-7H-furo[2,3-g]chromen-7-ones and 9-phenyl-7H-furo-[2,3-f]chromen-7-ones, new analogs of psoralen and allopsoralen, are synthesized from 7-hydroxy- and 5-hydroxy-4-phenylcoumarins
Coumarin derivative RKS262 belongs to a new class of potential anti-tumor agents. RKS262 was identified by structural optimization of Nifurtimox which is currently undergoing phase II clinical trials to treat high-risk neuroblastoma. In a NCI(60) cell-line assay RKS262 exhibited significant cytotoxicity in ovarian cancer cells and a variety of other cell lines exceeding effects of commercial drugs such as cisplatin, 5-FU, cyclophosphamide or sapacitabine. Various leukemia cell-lines were most sensitive (GI(50): ~ 10 nM) while several non-small cell lung cancer cell lines and few cell lines from other tissues were relatively resistant (GI(50) > 1 µM) to RKS262 treatment. The mechanism of cytotoxicity was examined using ovarian cancer cell-line OVCAR-3 as a model. RKS262 treatment resulted in a reduced mitochondria-transmembrane-depolarization potential. RKS262 effects included up-regulation of apoptotic markers and were not correlated with activation of pro-apoptotic MAP-Kinases (p38, SAP/JNK). RKS262 exerted strong inhibitory effects on oncogene ras, down-regulated DNA-pk KU-80 subunit expression and caused activation of Akt. A signature effect of RKS262 is the regulation of the mitochondrial Bcl2-family pathway. Pro-apoptotic factors Bid, Bad and Bok were up-regulated while expression of pro-survival factors Bcl-xl and Mcl-1 was inhibited. Moreover, at sub-cytotoxic doses RKS262 delayed OVCAR-3 cell-cycle progression through G2 phase and up-regulated p27 while cyclin-D1 and Cdk-6 were down-regulated, indicating that RKS262 is a specific cyclin/CDK inhibitor. In summary, RKS262 has been identified as a molecule belonging to a new class of potential chemotherapeutic agents affecting the viability of multiple cancer cell-lines and causing selective adverse effects on the viability of ovarian cancer cells.
The antidiabetic activity-guided fractionation and isolation of the 80% EtOH extracts from Peucedani Radix (Peucedanum japonicum, Umbelliferae) led to the isolation and characterization of a coumarin and a cyclitol as active principles, that is, peucedanol 7-O-beta-D-glucopyranoside (1) and myo-inositol (2). Their structures were identified by spectroscopic methods. Compound 1 showed 39% inhibition of postprandial hyperglycemia at 5.8 mg/kg dose, and compound 2 also significantly inhibited postprandial hyperglycemia by 34% (P<0.05).
A novel route for the efficient synthesis of a target psoralen moiety, 4,4′-dimethylxanthotoxol, has been developed, which need only four steps using cheap pyrogallol as a starting material. Subsequently, a range of new glycosylated psoralen derivatives were synthesized in good yields with simple procedures and mild reaction conditions. The experiment of biological activity shows that some of the glycosylated psoralen derivatives have antiproliferative activities against human cancer cell lines. A strong photo-induced antiproliferative effects were found under UVA. All of the glycosylated psoralen derivatives exhibited antioxidant activities against the oxidation of DNA induced by Cu2+/glutathione (GSH). Further experiment also demonstrates that the introduction of sugar moieties in some glycosylated psoralen derivatives can improve their antioxidant activities significantly.
3-(Chloromethyl)coumarins, obtained via acid-catalysed cyclisation of salicylaldehyde-derived Baylis-Hillman adducts, have been treated with propargylamine; reaction of the resulting 3-alkynylmethyl-coumarins with azidothymidine (AZT) in the presence of a Cu(I) catalyst has afforded a series of cycloaddition products for evaluation, in their own right, as potential dual-action HIV-1 protease and non-nucleoside reverse transcriptase inhibitors, and as scaffolds for further structural elaboration.
The mass spectra of coumarin, umbelliferone, herniarin, and ostol have been studied.
For Abstract see ChemInform Abstract in Full Text.
Frequently found in hydrocarbon oxidation and in the photochemistry of carbonyl compounds, the β-carbonyl radicals are of interest. The experimental proton affinities of the two title radicals have been determined from proton transfer reactions (as shown) monitored in an FT-ICR mass spectrometer. This led to an estimation of their heats of formation (1: 13±3; 2: -34±3 kJ mol(-1) ). Ab initio molecular orbital calculations, up to the G2 level, confirmed these results.
New grids for three‐dimensional numerical integration are introduced. They include a new mapping for radial integration of the Gauss–Chebyshev type which seems to surpass in accuracy the existing integration schemes as proposed by Becke [J. Chem. Phys. 88, 2547 (1988)], Murray et al. [Mol. Phys. 78, 997 (1993)], or Gill et al. [Chem. Phys. Lett. 209, 506 (1993)]. Lebedev grids are employed for spherical integration. Open ended quadrature schemes are presented using the efficient Lobatto formula for the θ integration. These grids are employed for self‐consistent density functional calculations using local approximation and nonlocal corrections and are implemented into the program package turbomole. The results of grid tests and demonstrative applications of energy and especially analytical gradient calculations are given. © 1995 American Institute of Physics.
Mass-spectrometric results for the coumarins, furocoumarins, and pyranocoumarins are summarised. The characteristic elimination of carbonyl groups characteristic of coumarin itself can be traced also in the spectra of substituted (halogenated, hydroxylated, methoxylated, carbonylated, O- and C-alkylated, and O- and C-acylated) coumarins, but the nature of the substituent has a decisive influence on the way in which derivatives break down, and in many cases elimination of carbonyl groups takes place only after partial or complete elimination of the substituent. With bicoumarins elimination of carbonyl groups is observed in the later stages of decomposition or not at all. The regularities reported for coumarins are found also with furo- and pyrano-coumarins. Differences in the spectra of positional isomers are usually apparent only in differences in the peak intensities of the characteristic ions.
There is a list of 59 references.
A study on the behavior of a large number of monomeric and dimeric coumarins in the mass spectrometer is reported and discussed. The results illustrate that the observed characteristic fragmentation patterns are of considerable utility in the application of mass spectrometry to structure elucidation in this series.
An investigation of the negative-ion chemistry of 13 coumarin and three psoralen compounds is reported. Negative-ion chemical ionization was effected using O−˙ and OH− as the reagent ions; it was found that O−˙ leads preferably to [M – H + O]− whereas OH− mainly furnishes [M – H]−. The results of metastable anion fragmentation and collision-induced dissociation of mass-selected anions are presented.
In order to study the effects of the precursor ion type and the carbohydrate structure on the fragmentation of neutral unsubstituted oligosaccharides in collision-induced dissociation (CID), a systematic study of deprotonated, protonated, ammoniated and alkali metal cationized cello-, malto- and xylooligosaccharides was carried out using a quadrupole ion trap (QIT) and Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry. The fragmentation pathway was highly dependent on the choice of the precursor ion type. Deprotonated precursors gave rise to both glycosidic and cross-ring fragmentation, with clear differences among the three oligosaccharides, therefore being the most prominent for structural analysis. The fragmentation behavior of the xylooligosaccharides differed from that of the cello- and maltooligosaccharides for all the precursor ions studied, most remarkably with the deprotonated and ammoniated precursors. Stereochemical differentiation of cello- and maltooligosaccharides was possible with the use of deprotonated, lithiated and sodiated precursors. In general, as the size of the alkali metal cation increased the amount of structurally informative cross-ring fragmentation increased, but the probability for metal ion loss from the precursor ion also increased. The CID spectra of xylooligosaccharides measured with the QIT and FT-ICR were surprisingly similar.
Alkylation of umbelliferone and nitrophenol with chloroacetone, 3-chlorobutanone, 2-chlorocyclopentanone and 2-chlorocyclohexanone gave the corresponding 2-coumaryloxy and 2-nitrophenoxy ketones. The 2-coumaryloxy ketones were used as fluorogenic substrates to detect Baeyer–Villiger monooxygenases activities of microbial cultures in high-throughput using microtiter plates. The 2-coumaryloxy ketones were oxidized by microorganisms producing Baeyer–Villiger monooxygenases (BVMO), releasing umbelliferone as a fluorescent signal. The substrates were also biotransformed by a microbial monooxygenase (Trichosporon cutaneum). Chemical Baeyer–Villiger oxidation of 2-coumaryloxy ketones using meta-chloroperbenzoic acid proceeded regioselectively to the corresponding acyloxyalkyl derivatives of umbelliferone and nitrophenol. These chiral lactones underwent a fluorogenic and chromogenic reaction upon hydrolysis by esterases, in particular pig liver esterase. Enantioselectivity of the ester hydrolysis reaction was determined by chiral-phase analysis of the unreacted lactones.
The field of electrospray ionization mass spectrometry is reviewed with emphasis placed upon advances in the elucidation of fundamental mechanistic aspects of the ionization process that have been reported over the past 10 years. The analytical consequences of these findings are also examined. Eight central conclusions or ‘tenets’ are presented, as deduced from the body of work contained in 80 references. Copyright © 2000 John Wiley & Sons, Ltd.
Phosphacoumarins and their 4-O-methylsulfonate derivatives, as the analogues of the coumarins with many biological activities, were synthesized, their fragmentation pathways were investigated by electrospray ionization mass spectrometry (ESI-MS) in conjunction with tandem mass spectrometry (MS/MS), and some characteristic fragment ions were observed by losing ethylene, water, CO, HPO 2 , HPO 3 , CH 3 SO 2 or CH 3 SO 2 H from the precursors.
Contracted Gaussian basis sets of triple zeta valence (TZV) quality are presented for Li to Kr. The TZV bases are characterized by typically including a single contraction to describe inner shells and three basis functions for valence shells. All parameters—orbital exponents and contraction coefficients—have been determined by minimization of atomic self-consistent field ground state energies. Advantages and necessary modifications of TZV basis sets are discussed for simple test calculations of molecular energies and nuclear magnetic resonance (NMR) chemical shieldings in treatments with and without inclusion of electron correlation. The Journal of Chemical Physics is copyrighted by The American Institute of Physics.
The basic structure of the program system TURBOMOLE for SCF - including first and second analytical derivatives with respect to nuclear coordinates - and MP2 calculations is briefly described. The program takes full advantage of all discrete point group symmetries and has only modest - and (partially) adjustable - I/O and background storage requirements. The performance of TURBOMOLE is documented for demonstrative applications.
Coumarins are a large group of compounds that are naturally present in plant tissues and that exhibit a wide range of pharmacological properties. Analytical methods based on chromatographic techniques and conventional detectors are inadequate to accurately analyze coumarins in complex matrices such as plant extracts. In this article a new method based on a modified particle beam liquid chromatography—mass spectrometry interface is described. The method allows specific and accurate determination of several coumarins in biological matrices. An application regarding the analysis of 18 coumarins in the extract of Smyrnium perfoliatum L. is also reported.
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
Electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) has been used for characterisation of a selection of naturally occurring and synthetic coumarins from different structural classes. The product ions, suggested in earlier studies by electrospray ionisation ion trap mass spectrometry (ESI-MS(n)), are unequivocally established for the representative coumarins by virtue of accurate mass measurement. Synthetic coumarins that are unsubstituted in the heterocyclic ring give rise to a major product ion by loss of CO(2), whereas those substituted in the heterocyclic ring generally undergo alternative fragmentation releasing neutral species such as ketene or methyl ketene. Naturally occurring coumarins, unsubstituted in the heterocyclic ring and substituted in the benzene ring with chains or rings of hydrocarbons and oxygen, principally fragment at the side chain releasing unsaturated hydrocarbons. The ESI-QTOF-MS/MS behaviour of some naturally occurring and synthetic quinolines which are structurally similar or fragment similarly are included where appropriate.
Twenty-two substituted 7-hydroxycoumarins were studied by negative ion electrospray ionization collision- induced dissociation (CID) mass spectrometry. Fragmentation pathways were also investigated by computation method using the B3LYP density functional theory. In general, the most important fragmentations of the 7- hydroxycoumarin [M - H](-) ions were the elimination of CO(2) and CO which agreed with the calculated energies of the proposed fragmentation reactions. In most cases, methyl group elimination was also favorable. Methyl group elimination occurred in three different ways, the most interesting being hydrogen rearrangement from a neighboring alkyl group to a ring carbon, which led to a benzyl radical formation. In some cases, CH(2)CO elimination was observed as well. Isomeric compounds gave rise to different CID spectra.
The mass spectra of columbianetin and its acetate, angelate, tiglate, and 3-bromo-angelate have been determined. Columbianetin shows M →188 →187 (base peak 187) as the principal fragmentation pathway whereas the esters show M → 228 → 213 (base peak 213) as the major fragmentation route. Probable mechanisms for fragmentation are suggested.
Phenylpropanoids are perhaps the most widespread types of natural products occurring in nature. In this account of the chemistry and utilization of phenylpropanoids we emphasize a few of the useful physiological, pharmacological, and chemical properties of flavonoids, lignans, and coumarins which are three of the major classes of compounds containing the C6-C3 phenylpropanoid moiety.
A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity to Kv1.2. 5,8-Diethoxypsoralen (10d) was found to be an equally potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1. 3.
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
The electrospray ionisation (ESI) of selected coumarin derivatives and their subsequent fragmentation using an ion trap mass spectrometer have been investigated. Sequential product ion fragmentation experiments (MS(n)) were performed in order to elucidate the degradation pathways for these compounds. A comparison was also made between these ESI spectra and those obtained under electron impact (EI) conditions. The data presented in this paper provides useful information on the effect of different substituents on the ionisation/fragmentation processes and can be used in the characterisation of these compounds.
The term "wrong-way-round ionization" has been used in studies of electrospray ionization to describe the observation of protonated or deprotonated ions when sampling strongly basic or acidic solutions (respectively) where such ions are not expected to exist in appreciable concentrations in solution. Study of the dependence of ionization of the weak base caffeine on the electrospray capillary potential reveals three distinct contributors to wrong-way-round ionization. At near-neutral pH in solutions of low ionic strength, protonation of caffeine results from the surface enrichment of electrolytically produced protons in the surface layer of the droplets from which ions are desorbed. For solutions made strongly basic with ammonia, gas-phase proton transfer from ammonium ions can create protonated caffeine. These two mechanisms have been discussed previously elsewhere. For solutions of high ionic strength at neutral or high pH, the data suggest that discharge-induced ionization is responsible for the production of protonated caffeine. This mechanism probably accounts for some of the wrong-way-round ionization reported elsewhere.
Electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) methods were used to study open-chain piperazine-containing ligands (L) and their complexes formed with transition-metal salts. ESI and MALDI measurements were performed with a Fourier transform ion cyclotron resonance (FT-ICR) and a time-of-flight (TOF) mass spectrometer, respectively. Only singly charged complexes, between one ligand and one or several metal ions, were formed in the ESI measurements. Because the net charge was always one, one or several counterions were attached to the complex. Under ESI conditions, the complexes formed between the ligands and metal (Co, Ni, Cu, and Cd) salts were [L + M + X](+), [L + H + M + X(2)](+) and [L + M(2) + X(3)](+) (M = metal ion, X = counterion). In collision induced dissociation reactions the [L + H + M + X(2)](+) complexes easily eliminated one proton and one counterion. Fragmentation pathways were more dependent on the metal ion than the ligand, and elimination of the second counterion occurred with one proton from copper and nickel complexes and with one proton and one hydrogen from cobalt complexes. Differences in the fragmentation of the complexes could be due to electronic configuration of the metal ion. In the MALDI measurements the ratio between the [L + H](+) and [L - H](+) ions varied with the matrix. Fragmentation of the ligands through elimination of 2-methylpyridine end groups occurred with the aromatic matrices containing carboxylic acid and hydroxyl substituents. Ionization of the complexes was not successful with MALDI as the matrix molecules were also attached to the complexes.
The reported effects of grapefruit (Citrus paradisi Macf.) juice on oral bioavailability of certain prescription drugs have led to the discovery of the inhibition by compounds in grapefruit of cytochrome P450 3A4 (CYP3A4) in the intestinal wall and liver. Recent evidence indicates that furanocoumarins related to bergamottin [5-[(3',7'-dimethyl-2',6'-octadienyl)oxy]psoralen] are primarily responsible for the grapefruit effect, yet the exact mechanisms and roles that specific compounds play in this effect are still uncertain. In the current experiments freshly extracted grapefruit juice was separated into four fractions, consisting of raw finished juice (approximately 5% fine pulp), centrifugal retentate (approximately 35% fine pulp), centrifuged supernatant (<1% pulp), and coarse finisher pulp. The relative concentrations of furanocoumarins in each of these grapefruit juice fractions were measured by HPLC-MS. These measurements showed that the centrifugal retentate had the highest furanocoumarin content, containing 892 ppm of bergamottin, 628 ppm of 6',7'-dihydroxybergamottin, 116 ppm of 6',7'-epoxybergamottin, 105 ppm of 7-geranyloxycoumarin, and approximately 467 ppm of furanocoumarin dimers. These high furanocoumarin concentrations make this fraction a useful starting material for preparative-scale isolations of these compounds. MS analysis of this furanocoumarin-enriched fraction provided evidence of additional furanocoumarins in grapefruit juice that remain to be fully characterized and evaluated for their roles in the grapefruit-drug interactions.
The collision-induced dissociations of the even-electron [M + H](+) and/or [M - H](-) ions of 121 model compounds (mainly small aromatic compounds with one to three functional groups) ionized by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) have been studied using an ion trap instrument, and the results are compared with the literature data. While some functional groups (such as COOH, COOCH(3), SO(3)H in the negative ion mode, or NO(2) in both the positive and negative ion modes) generally promote the loss of neutrals that are characteristic as well as specific, other functional groups (such as COOH in the positive ion mode) give rise to the loss of neutrals that are characteristic, but not specific. Finally, functional groups such as OH and NH(2) in aromatic compounds do not lead to the loss of a neutral that reflects the presence of these substituents. In general, the dissociation of [M + H](+) and [M - H](-) ions generated from aliphatic compounds or compounds containing an aliphatic moiety obeys the even-electron rule (loss of a molecule), but deviations from this rule (loss of a radical) are sometimes observed for aromatic compounds, in particular for nitroaromatic compounds. Thermochemical data and ab initio calculations at the CBS-QB3 level of theory provide an explanation for these exceptions. When comparing the dissociation behaviour of the even-electron [M + H](+) and/or [M - H](-) ions (generated by ESI or APCI) with that of the corresponding odd-electron [M](+) ions (generated by electron ionization, EI), three cases may be distinguished: (1) the dissociation of the two ionic species differs completely; (2) the dissociation involves the loss of a common neutral, yielding product ions differing in mass by one Da, or (3) the dissociations lead to a common product ion.
Type 2 diabetes is associated with altered regional blood flow and expression of nitric oxide synthase (NOS). We examined the functional role of constitutive and inducible NOS synthase (cNOS and iNOS, respectively) on regional blood flow in thiobutabarbital-anesthetized Zucker diabetic fatty (ZDF) and control rats via the radioactive microspheres technique. Blood flow was measured at baseline (1 h after surgery), after i.v. administration of 1400W (N-3-aminomethyl-benzyl-acetamidine, selective iNOS inhibitor, 3 mg/kg), and again after i.v. N(G)-nitro-l-arginine methyl ester (L-NAME, non-selective NOS inhibitor, 8 mg/kg). Both groups had similar baseline mean arterial pressure, cardiac output and total peripheral resistance, but the ZDF rats had lower heart rate relative to the control rats (272 versus 305 beats/min). Whereas 1400W did not alter mean arterial pressure or blood flow in either group, L-NAME markedly increased mean arterial pressure and total peripheral resistance, and reduced cardiac output, heart rate, blood flow and arterial conductance in all organs/tissues of both the control and ZDF rats. L-NAME caused greater vasoconstriction in the heart (1.5-times the constriction in control rats) and brain (1.5-times) of the ZDF rats, but less in the pancreas (0.6-times). Thus, cNOS had greater vasodilator control of the heart and brain, but less in the pancreas of the ZDF than control rats. iNOS has negligible influence on blood flow in both groups of rats.
E-mail: janne.janis@uef.fi Copyright ©
- Joensuu
- Finland
Joensuu, Finland. E-mail: janne.janis@uef.fi Copyright © 2013 John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom. 2013, 27, 2665–2675 Research Article Received: 30 April 2013
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