Liquid chromatography-mass spectrometry as a general approach for investigating covalent binding of drugs to DNA

Maria Raja, Joan Albertí, Javier Saurina, Sonia Sentellas

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

© 2016, Springer-Verlag Berlin Heidelberg. This paper aims at developing a general strategy to study the detection of adducts of drugs with DNA. In particular, ethacrynic acid has been chosen as a model reactive drug that could be able to bind covalently to DNA bases. Such interactions were detected by ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Principal component analysis (PCA) was applied as an unsupervised method to try to find the potential candidate adduct from MS features. The occurrence of adducts was investigated preliminarily using deoxynucleosides of the guanine, cytosine, adenine, and thymine separately as a way to optimize both separation and detection conditions. Interpretations of MS and MS/MS spectra provided tentative structures of the compounds formed. Conclusions extracted from such simple nucleoside models were further extended to the analysis of DNA adducts. For such a purpose, DNA was incubated in the presence of ethacrynic acid under appropriate experimental conditions and its further enzymatic hydrolysis released the corresponding nucleosides. UHPLC-MS analysis of the resulting test samples under the SRM detection mode confirmed the presence of ethacrynic acid derivatives of nucleosides occurring at very low concentration levels, thus proving the overall performance of the method. [Figure not available: see fulltext.]
Original languageEnglish
Pages (from-to)3911-3922
JournalAnalytical and Bioanalytical Chemistry
Volume408
Issue number14
DOIs
Publication statusPublished - 1 May 2016

Keywords

  • Deoxynucleoside adduct
  • DNA adduct
  • High resolution mass spectrometry
  • Principal component analysis
  • UHPLC

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