Desorption chemical ionization mass spectrometry of anthracyclines and of trisaccharides related to aclacinomycin a and marcellomycin

Monneret, Claude; Sellier, Nicole

doi:10.1002/bms.1200130702

Cited by 14 publications

(5 citation statements)

References 12 publications

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“…() used the SRM transition of m/z 544 to m/z 361 for the measurement of doxorubicin, we used this transition as the qualifier and added the SRM transition of m/z 544 to m/z 397 as the quantifier. As reported previously (Monneret and Sellier ), the initial site of protonation of anthracycline antibiotics like doxorubicin occurs primarily on the oxygen of the glycosidic bond, resulting in abundant fragmentation at that position with the oxygen atom remaining on the sugar moiety to form the doxorubicin product ion of m/z 397.…”

Section: Resultssupporting

confidence: 58%

Confirmation of drug delivery after liver chemoembolization: direct tissue doxorubicin measurement by UHPLC‐MS‐MS

Baumgarten

Gaba

Breemen

2012

Biomedical Chromatography

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Because liver cancer is rarely suitable for surgery, transcatheter arterial chemoembolization (TACE) is used for palliative therapy. In this procedure, an emulsion of doxorubicin in iodized oil is injected directly into liver tumors through a catheter positioned within the artery supplying blood flow to the tumor. At present, there is limited understanding of factors affecting the delivery and dispersion of doxorubicin within treated tumors during TACE. This study addresses the development and application of an ultrahigh pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS) method for rapid confirmation of drug delivery after TACE in a rabbit VX2 liver cancer model. Doxorubicin levels in liver tumors were measured using UHPLC-MS-MS and compared with computed tomography measured levels of iodized oil, a metric used clinically to indicate drug delivery. We found that tissue drug levels determined using UHPLC-MS-MS did not correlate with the regional iodized oil concentration (vehicle) within tumors following TACE, suggesting that chemotherapeutic drugs like doxorubicin spread throughout tumors, and that lack of iodized oil staining in portions of a tumor does not necessarily indicate inadequate therapy during TACE.

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Section: Resultssupporting

confidence: 58%

Confirmation of drug delivery after liver chemoembolization: direct tissue doxorubicin measurement by UHPLC‐MS‐MS

Baumgarten

Gaba

Breemen

2012

Biomedical Chromatography

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“…3 We have measured mass spectra (electrospray ionization and MALDI) of DNR and DNR oxidized by LPO/H2O2/NO2in the m/z range of 100-800. The spectra showed the presence of molecular ions (M+H) + of m/z 528 (parent molecule), 383 (aglycon), 363 (aglycon with aromatized ring A), 337, 321, which are characteristic of fragmentation of an intact DNR (70,71). In the sample containing oxidized DNR, relative peak intensities for ions at m/z 321 and 363 were markedly decreased, and the ion at 528 was absent.…”

Section: Discussionmentioning

confidence: 99%

Peroxidase- and Nitrite-Dependent Metabolism of the Anthracycline Anticancer Agents Daunorubicin and Doxorubicin

2001

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Oxidation of the anticancer anthracyclines doxorubicin (DXR) and daunorubicin (DNR) by lactoperoxidase(LPO)/H(2)O(2) and horseradish peroxidase(HRP)/H(2)O(2) systems in the presence and absence of nitrite (NO(2)(-)) has been investigated using spectrophotometric and EPR techniques. We report that LPO/H(2)O(2)/NO(2)(-) causes rapid and irreversible loss of anthracyclines' absorption bands, suggesting oxidative degradation of their chromophores. Both the initial rate and the extent of oxidation are dependent on both NO(2)(-) concentration and pH. The initial rate decreases when the pH is changed from 7 to 5, and the reaction virtually stops at pH 5. Oxidation of a model hydroquinone compound, 2,5-di-tert-butylhydroquinone, by LPO/H(2)O(2) is also dependent on NO(2)(-); however, in contrast to DNR and DXR, this oxidation is most efficient at pH 5, indicating that LPO/H(2)O(2)/NO(2)(-) is capable of efficiently oxidizing simple hydroquinones even in the neutral form. Oxidation of anthracyclines by HRP/H(2)O(2)/NO(2)(-) is substantially less efficient relative to that by LPO/H(2)O(2)/NO(2)(-) at either pH 5 or pH 7, most likely due to the lower rate of NO(2)(-) metabolism by HRP/H(2)O(2). EPR measurements show that interaction of anthracyclines and 2,5-di-tert-butylhydroquinone with LPO/H(2)O(2)/NO(2)(-) generates the corresponding semiquinone radicals presumably via one-electron oxidation of their hydroquinone moieties. The possible role of the (*)NO(2) radical, a putative LPO metabolite of NO(2)(-), in oxidation of these compounds is discussed. Because in vivo the anthracyclines may co-localize with peroxidases, H(2)O(2), and NO(2)(-) in tissues, their oxidation via the proposed mechanism is likely. These observations reveal a novel, peroxidase- and nitrite-dependent mechanism for the oxidative transformation of the anticancer anthracyclines, which may be pertinent to their biological activities in vivo.

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“…The exact same fragmentation pattern characterizes the low collision energy HCD MS/MS spectra of conjugates 5 and 6 (Figure S1B,C). Cleavage mechanism of the glycosidic bond according to the literature[25], and the fragmentation scheme proposed herein for the loss of Dau moiety by the breakage of the oxime bond.Corresponding neutral fragments formed upon the cleavages of the glycosidic or oxime bonds are present but are not depicted for the ease of readability. Neutral losses are marked as follows: * = sugar, ° = H2O, # = Dau + sugar.…”

mentioning

confidence: 99%

“…Cleavage mechanism of the glycosidic bond according to the literature[25], and the fragmentation scheme proposed herein for the loss of Dau moiety by the breakage of the oxime bond. Corresponding neutral fragments formed upon the cleavages of the glycosidic or oxime bonds are present but are not depicted for the ease of readability.…”

mentioning

confidence: 99%

Structural Characterization of Daunomycin-Peptide Conjugates by Various Tandem Mass Spectrometric Techniques

Borbély

Pethő

Szabó

et al. 2021

IJMS

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The use of peptide-drug conjugates has generated wide interest as targeted antitumor therapeutics. The anthracycline antibiotic, daunomycin, is a widely used anticancer agent and it is often conjugated to different tumor homing peptides. However, comprehensive analytical characterization of these conjugates via tandem mass spectrometry (MS/MS) is challenging due to the lability of the O-glycosidic bond and the appearance of MS/MS fragment ions with little structural information. Therefore, we aimed to investigate the optimal fragmentation conditions that suppress the prevalent dissociation of the anthracycline drug and provide good sequence coverage. In this study, we comprehensively compared the performance of common fragmentation techniques, such as higher energy collisional dissociation (HCD), electron transfer dissociation (ETD), electron-transfer higher energy collisional dissociation (EThcD) and matrix-assisted laser desorption/ionization–tandem time-of-flight (MALDI-TOF/TOF) activation methods for the structural identification of synthetic daunomycin-peptide conjugates by high-resolution tandem mass spectrometry. Our results showed that peptide backbone fragmentation was inhibited by applying electron-based dissociation methods to conjugates, most possibly due to the “electron predator” effect of the daunomycin. We found that efficient HCD fragmentation was largely influenced by several factors, such as amino acid sequences, charge states and HCD energy. High energy HCD and MALDI-TOF/TOF combined with collision induced dissociation (CID) mode are the methods of choice to unambiguously assign the sequence, localize different conjugation sites and differentiate conjugate isomers.

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Desorption chemical ionization mass spectrometry of anthracyclines and of trisaccharides related to aclacinomycin a and marcellomycin

Cited by 14 publications

References 12 publications

Confirmation of drug delivery after liver chemoembolization: direct tissue doxorubicin measurement by UHPLC‐MS‐MS

Confirmation of drug delivery after liver chemoembolization: direct tissue doxorubicin measurement by UHPLC‐MS‐MS

Peroxidase- and Nitrite-Dependent Metabolism of the Anthracycline Anticancer Agents Daunorubicin and Doxorubicin

Structural Characterization of Daunomycin-Peptide Conjugates by Various Tandem Mass Spectrometric Techniques

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