Are liquid chromatography/electrospray tandem quadrupole fragmentation ratios unequivocal confirmation criteria?

Kaufmann, Anton; Butcher, Patrick; Maden, Kathryn; Widmer, Mirjam; Giles, Kevin; Uria, Diana

doi:10.1002/rcm.3959

Cited by 77 publications

(93 citation statements)

References 18 publications

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“…The selectivity was further confi rmed by determining the branching ratio of the mass transitions from six individual blank plasma samples within 10% of the value of the calibrator (prepared in methanol-water, 1:1). The branching ratio is the ratio of peak areas of two mass transitions of 3 ␤ ,5 ␣ ,6 ␤ -triol (591 → 104/591 → 488) and 7-KC (486 → 383/486 → 104), and was used to assure specifi city of the detection (24)(25)(26). The branching ratios of six individual blank plasma samples were compared with the ratios of the same transitions in the ULOQ calibrator containing 400 ng/ml 3 ␤ ,5 ␣ ,6 ␤ -triol and 7-KC (supplementary Table I).…”

Section: Oxysterol Derivatization With Dimethylglycinementioning

confidence: 99%

A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma

Jiang

Sidhu

Porter

et al. 2011

Journal of Lipid Research

233

186

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Supplementary key words cholesterol • diagnostic tools • liquid chromatography/tandem mass spectrometry • Niemann-Pick disease • oxysterols • neurodegenerationNiemann-Pick type C (NPC) disease is a rare, primarily pediatric disorder characterized by accumulation of cholesterol and other lipids in the viscera and central nervous system. Approximately 95% of NPC cases are caused by mutations of the NPC1 gene, whereas the remaining 5% are caused by mutations in the NPC2 gene ( 1, 2 ). Affected individuals typically present in early childhood with ataxia and progressive impairment of motor and intellectual function and usually die in adolescence. There are currently no FDA-approved therapies for this progressively fatal neurodegenerative disorder. However, a recent controlled study and a series of case reports suggests effi cacy for miglustat ( 3 ), an inhibitor of glycosphingolipid biosynthesis that is now licensed for use as a disease modifying therapy in multiple countries, including the European Union, Russia, Brazil, Australia, Canada, and Taiwan.Abstract Niemann-Pick type C1 (NPC1) disease is a rare, progressively fatal neurodegenerative disease for which there are no FDA-approved therapies. A major barrier to developing new therapies for this disorder has been the lack of a sensitive and noninvasive diagnostic test. Recently, we demonstrated that two cholesterol oxidation products, specifi cally cholestane-3 ␤ ,5 ␣ ,6 ␤ -triol (3 ␤ ,5 ␣ ,6 ␤ -triol) and 7-ketocholesterol (7-KC), were markedly increased in the plasma of human NPC1 subjects, suggesting a role for these oxysterols in diagnosis of NPC1 disease and evaluation of therapeutics in clinical trials. In the present study, we describe the development of a sensitive and specifi c LC-MS/ MS method for quantifying 3 ␤ ,5 ␣ ,6 ␤ -triol and 7-KC human plasma after derivatization with N,N-dimethylglycine. We show that dimethylglycine derivatization successfully enhanced the ionization and fragmentation of 3 ␤ ,5 ␣ ,6 ␤ -triol and 7-KC for mass spectrometric detection of the oxysterol species in human plasma. The oxysterol dimethylglycinates were resolved with high sensitivity and selectivity, and enabled accurate quantifi cation of 3 ␤ ,5 ␣ ,6 ␤ -triol and 7-KC concentrations in human plasma. The LC-MS/MS assay was able to discriminate with high sensitivity and specifi city between control and NPC1 subjects, and offers for the fi rst time a noninvasive, rapid, and highly sensitive method for diagnosis of NPC1

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Section: Oxysterol Derivatization With Dimethylglycinementioning

confidence: 99%

A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma

Jiang

Sidhu

Porter

et al. 2011

Journal of Lipid Research

233

186

View full text Add to dashboard Cite

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“…We explain these findings with the presence of protonation site isomers (protomers), which originate from the ionization and desolvation process in the interface of the instrument, and therefore have no physiological relevance as a functional analyte. Protomer separation is thought to be the result of interactions between the dipole moment of the ion, resulting from its charge distribution, and polarizable gas molecules, which lead to an additional retardation of ion movement through the drift gas [43,44,55,59]. A more detailed study of melphalan protomers has been published recently [26].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the presence of a second drift time must be inherent to the gasphase properties of the molecule and/or the ion mobility separation itself. A study by Kaufmann et al [55] reports on the existence of two ion types for the pesticide norfloxacin. These "isobaric ions" have identical retention times and exact masses, but appear to have different gas-phase properties.…”

Section: Observation Of Multiple Drift Times For Melphalanmentioning

confidence: 99%

Analyzing complex mixtures of drug-like molecules: Ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods

Boschmans

Lemière

Sobott

2017

Journal of Chromatography A

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Please cite this article as: Jasper Boschmans, Filip Lemière, Frank Sobott, Analyzing complex mixtures of drug-like molecules: ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods, Journal of Chromatography A http://dx.doi.org/10. 1016/j.chroma.2017.02.015 This is a PDF Þle of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its Þnal form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe use of traveling wave ion mobility mass spectrometry (TWIMS) is evaluated in conjunction with, and as a possible alternative to, conventional LC-MS(/MS) methods for the separation and characterization of drug-like compounds and metabolites. As a model system we use an in vitro incubation mixture of the chemotherapeutic agent melphalan, which results in more than ten closely related hydrolysis products and chain-like oligomers. Ion mobility as a filtering tool results in the separation of ions of interest from interfering ions, based on charge state and shape/size. Different classes of chemical compounds often display different mobilities even if they show the same LC behavior -thereby providing an orthogonal separation dimension. Small molecules with identical or similar m/z that only differ in shape/size (e.g. isomers and isobars, monomers/dimers) can also be distinguished using ion mobility. Similar to retention times and mass-to-charge ratios, drift times are analyte-dependent and can be used as an additional identifier. We find that the compound melphalan shows two different drift times due to the formation of gas-phase charge isomers (protomers). The occurrence of protomers has important implications for ion mobility characterization of such analytes, and also for the interpretation of their fragmentation behavior (CID) in the gas phase.

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“…In conclusion, the MS 2 fragmentation pattern of olanzapine glucuronides and the proton affinity of model compounds could explain that in 3, the N-2 was protonated and that therefore almost no loss of 134 Da was observed. Other examples, where the site of the protonation influenced the MS/MS fragmentation pattern, have been described (Kaufmann et al 2009;Wang et al 2010). …”

Section: Discussionmentioning

confidence: 99%

Human UDP-glucuronosyltransferase UGT1A4 forms tertiary N-glucuronides predominately with the energetically less favored tautomer of substituted 1H-indazole (benzpyrazole)

et al. 2017

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Background: Human UDP-glucuronosyltransferase UGT1A4 is reported to convert a range of tertiary amine substrates to the respective quaternary glucuronides. In this study, we report on the in vitro glucuronidation of a substituted 1H-indazole (benzpyrazole), a transient receptor potential ankyrin 1 antagonist. Methods: Depending on the mammalian liver used for production, two peaks with different UV spectra and slightly different MS/MS spectra were found in the LC-MS/MS analysis. An optimized HPLC method gave a baseline separation of the two glucuronides. Preparation and isolation allowed to assign their structure by 1 H-, 13 C-, and 15 N-NMR.

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Are liquid chromatography/electrospray tandem quadrupole fragmentation ratios unequivocal confirmation criteria?

Cited by 77 publications

References 18 publications

A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma

A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma

Analyzing complex mixtures of drug-like molecules: Ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods

Human UDP-glucuronosyltransferase UGT1A4 forms tertiary N-glucuronides predominately with the energetically less favored tautomer of substituted 1H-indazole (benzpyrazole)

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