Binding of Antitumor Metallocenes to Nucleic Acids

Eberle, Rahel Patricia (2018). Binding of Antitumor Metallocenes to Nucleic Acids. (Dissertation, Department of Chemistry and Biochemistry, Faculty of Sciences)

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Cancer is a severe disease that is responsible for the annual death of millions of people worldwide. For decades, the most prominent approach to inhibit the rapid growth of cancer cells has been the administration of platinum-based anticancer drugs, such as cisplatin and its newer generation derivatives. These agents bind to nuclear DNA and thus, interfere with cell replication. However, the drugs suffer from severe side effects. The search for potent chemotherapeutic agents that represent an alternative to platinum-related compounds led to the synthesis of numerous DNA-binding metallodrugs. Metallocenes and their derivatives are a class of such antitumor complexes that target nucleic acids. For the investigation of their interaction with DNA, powerful and reliable analytical methods are needed. High-resolution tandem mass spectrometry constitutes a versatile technique for the structural characterization of nucleic acid-drug complexes and for the localization of the preferred binding sites.

In the first part of this thesis the investigation of the binding of metallocenes to deoxydinucleoside monophosphates is reported. The binding was found to essentially depend on the type of transition metal, following Pearsons' hard and soft Lewis acids and bases concept. The metallocenes based on the hard Lewis acids titanium and vanadium were found to primarily bind to the phosphate oxygen, while the softer molybdenum additionally interacts with the nucleobases. No interaction with DNA was found for niobocene, which indicates a different mechanism of action. Studies on hexanucleotides revealed that hard Lewis acids bind to phosphate groups in a nucleobase- and sequencedependent manner. Since the phosphate group adjacent to a thymine exhibits the highest acidity, it constitutes the preferred binding site for metallocenes comprising a hard Lewis acid coordination center.

While cationic adducts dissociated via backbone cleavage, thus, enabling to localize favored binding sites, adduct anions released both cylcopentadienyl ligands upon collision-induced dissociation (CID) and only minor backbone scission occurred. The loss of the ligands was found to be accompanied by electron transfer from one cyclopentadienyl ligand to the remaining metallated adduct. To gain deeper insight into this unusual electron transfer process, the adducts were analyzed by electron transfer dissociation (ETD) and by ETD in combination with CID (ETcaD). Results revealed the nucleobase rather than the metal center as preferred site for electron transfer.

In summary, the presented work represents the first mass spectrometry-based elucidation of the interaction of anticancer metallocenes with their DNA target and thereby contributes to a deeper understanding of their unique binding characteristics.

Item Type:

Thesis (Dissertation)


08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Eberle, Rahel, Schürch, Stefan


500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
500 Science


[UNSPECIFIED] Department of Chemistry and Biochemistry




Stefan Schürch

Date Deposited:

19 Sep 2019 13:43

Last Modified:

05 Dec 2022 15:29




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