A major part of our research is the investigation of adducts formed between nucleic acids and cytotoxic agents, such as cis-diamminedichloroplatinum(II) (cisplatin, DDP). Cisplatin is still the most widely used chemotherapeutic agent in oncology world-wide. Its cytotoxic effect is based on the formation of 1,2-intrastrand adducts at adjacent guanine nucleobases in DNA and RNA, thus, causing distortion of the double-strand and inhibiting translation. Mass spectrometric analysis of these adducts yields information on the specificity of the reagent, the stoichiometry of the reaction, and provides the armory for a rapid and unambiguous localization of adduct sites. The application of modern analytical techniques for elucidation of the modes of action of anti-cancer drugs can greatly accelerate biomedical research.
The binding of titanocene to DNA and RNA was examined by means of electrospray mass spectrometry. Titanocene served as a model for its therapeutically active derivatives. The binding preferences were probed by competition experiments with oligonucleotides of varying nucleobase compositions and sequences. Results from competition experiments revealed a generally increased preference for the binding to phosphate groups adjacent to thymidines, which is affected by the nucleobase sequence of T-rich oligonucleotides. The binding of the transition metal coordination center significantly altered the fragment ion patterns of the oligonucleotides in tandem mass spectrometric experiments. RNA was found to be less prone to adduct formation, due to intramolecular interactions. The findings from experiments on DNA and RNA were complemented by the examination of backbone- and ribose-modified oligonucleotides.
R. Eberle, S. Schürch. Titanocene Binding to Oligonucleotides. J. Inorg. Biochem., 2018, 184, 1-7. 10.1016/j.jinorgbio.2018.03.014.
R. Eberle, Y. Hari, S. Schürch. Specific Interactions of Antitumor Metallocenes with Deoxydinucleoside Monophosphates. J. Am. Soc. Mass Spectrom. 2017, 28, 1901-1909. 10.1007/s13361-017-1697-9.
Y. Hari, A. Nyakas, S. R. Stucki, S. Schürch. Elucidation of nucleic acid - drug interactions by tandem mass spectrometry. Chimia. 2014, 68, 164-167. 10.2533/chimia.2014.164
A. Nyakas, S. R. Stucki, S. Schürch. Tandem Mass Spectrometry of Modified and Platinated Oligoribonucleotides. J. Am. Soc. Mass Spectrom. 2011, 22, 875-887. 10.1007/s13361-011-0106-z
S. R. Stucki, A. Nyakas, S. Schürch. Tandem mass spectrometry of platinated quadruplex DNA. Int. J. Mass Spectrom. 2011, 46, 1288-1297. 10.1002/jms.2019
A. Nyakas, M. Eymann, S. Schürch. The Influence of Cisplatin on the Gas-Phase Dissociation of Oligonucleotides Studied by Electrospray Ionization Tandem Mass Spectrometry. J. Am. Soc. Mass Spectrom. 2009, 20, 792-804.