The influence of cisplatin on the gas-phase dissociation of oligonucleotides studied by electrospray ionization tandem mass spectrometry |
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Authors: | Adrien Nyakas Michael Eymann Stefan Schürch |
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Institution: | (1) Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland; |
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Abstract: | 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. |
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Keywords: | |
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