Specific Interactions of Antitumor Metallocenes with Deoxydinucleoside Monophosphates
| Autor: | Yvonne Hari, Rahel Patricia Eberle, Stefan Schürch |
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| Rok vydání: | 2017 |
| Předmět: |
Stereochemistry
Metallocenes Metal ions in aqueous solution Inorganic chemistry Vanadium chemistry.chemical_element Antineoplastic Agents 010402 general chemistry 01 natural sciences Nucleobase Adduct chemistry.chemical_compound Deprotonation Structural Biology Tandem Mass Spectrometry 540 Chemistry Lewis acids and bases Spectroscopy Lewis Acids 010405 organic chemistry Chemistry 500 Science 0104 chemical sciences HSAB theory 570 Life sciences biology Metallocene Dinucleoside Phosphates |
| Zdroj: | J. Am. Soc. Mass Spectrom. |
| ISSN: | 1879-1123 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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