Specific Interactions of Antitumor Metallocenes with Deoxydinucleoside Monophosphates

Eberle, Rahel P.; Hari, Yvonne Ilona; Schürch, Stefan (2017). Specific Interactions of Antitumor Metallocenes with Deoxydinucleoside Monophosphates. Journal of the American Society for Mass Spectrometry, 28(9), pp. 1901-1909. Springer 10.1007/s13361-017-1697-9

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Bent metallocenes Cp2MCl2 (M = Ti, V, Nb, Mo) are known to exhibit cytotoxic activity against a variety of cancer types. Though the mechanism of action is not fully understood yet, the accumulation of the metal ions in the nucleus points towards DNA as one of the primary targets. A set of eight deoxydinucleoside monophosphates was used to study the adduct yields with metallocenes and cisplatin. The binding affinities are reflected by the relative intensities of the adducts and were found to follow the order of Pt > V > Ti > Mo (no adducts were detected with Nb). High-resolution tandem mass spectrometry was applied to locate the binding patterns in the deoxydinucleoside monophosphates. Whereas cisplatin binds to the soft nitrogen atoms in the purine nucleobases, the metallocenes additionally interact with the hard phosphate oxygen, which is in good agreement with the hard and soft (Lewis) acids and bases (HSAB) concept. However, the binding specificities were found to be unique for each metallocene. The hard Lewis acids titanium and vanadium predominantly bind to the deprotonated phosphate oxygen, whereas molybdenum, an intermediate Lewis acid, preferentially interacts with the nucleobases. Nucleobases comprise alternative binding sites for titanium and vanadium, presumably oxygen atoms for the first and nitrogen atoms for the latter. In summary, the intrinsic binding behavior of the different metallodrugs is reflected by the gas-phase dissociation of the adducts. Consequently, MS/MS can provide insights into therapeutically relevant interactions between metallodrugs and their cellular targets.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Hari, Yvonne Ilona and Schürch, Stefan

Subjects:

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

ISSN:

1044-0305

Publisher:

Springer

Funders:

[42] Schweizerischer Nationalfonds

Language:

English

Submitter:

Stefan Schürch

Date Deposited:

13 Apr 2018 15:38

Last Modified:

13 Apr 2018 15:43

Publisher DOI:

10.1007/s13361-017-1697-9

PubMed ID:

28500584

BORIS DOI:

10.7892/boris.112531

URI:

https://boris.unibe.ch/id/eprint/112531

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