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The influence of cisplatin on the gas-phase dissociation of oligonucleotides studied by electrospray ionization tandem mass spectrometry

Nyakas, Adrien ; Eymann, Michael ; Schürch, Stefan

In: Journal of the American Society for Mass Spectrometry, 2009, vol. 20, no. 5, p. 792-804

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    Titre
    • The influence of cisplatin on the gas-phase dissociation of oligonucleotides studied by electrospray ionization tandem mass spectrometry
    Auteur
    • Nyakas, Adrien. Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland
    • Eymann, Michael. Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland
    • Schürch, Stefan. Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • Journal of the American Society for Mass Spectrometry, 2009, vol. 20, no. 5, p. 792-804. Springer-Verlag
    Autre version électronique
    Classification
    • Chimie
    Identifiant OAI-PMH
    • oai:doc.rero.ch:311423
    Summary
    cis-Diamminedichloroplatinum(II) (cisplatin, DDP) is a cornerstone of anticancer therapy and has become one of the most widely used drugs for the treatment of various epithelial malignancies. The cytotoxicity of cisplatin is mainly based upon its affinity to adjacent guanines in nucleic acids, resulting in the formation of 1,2-intrastrand adducts. In this study the gas-phase dissociation of DNA- and RNA-cisplatin adducts is investigated by electrospray ionization (ESI) tandem mass spectrometry (MS/MS). The fundamental mechanistic aspects of fragmentation are elucidated to provide the basis for the tandem mass spectrometric determination of binding motifs and binding sites of this important anticancer drug. It is shown that the binding of cisplatin to vicinal guanines drastically alters the gas-phase fragmentation behavior of oligonucleotides. The 3′-C-O bond adjacent to the GG base pair is preferentially cleaved, leading to extensive formation of the corresponding w-ion. This observation was even made for oligoribonucleotides, which usually tend to form c- and y-ions under CID conditions. The absence of complementary ions of equal abundance indicates that oligonucleotide-cisplatin adducts are following more than one dissociation pathway in the gas-phase. Several mechanisms that explain the increased cleavage of the 3′-C-O bond and the lack of the complementary a-ion are proposed. Results of additional MS/MS experiments on methylphosphonate-oligodeoxynucleotides confirm the proposed mechanisms