Tandem Mass Spectrometric Analysis of Metallocene Adducts with Short Oligonucleotides

Eberle, Rahel Patricia; Schürch, Stefan (29 October 2015). Tandem Mass Spectrometric Analysis of Metallocene Adducts with Short Oligonucleotides (Unpublished). In: Meeting of the Swiss Group for Mass Spectrometry. Beatenberg. 29./30.10.2015.

Official URL: http://www.sgms.ch

Metallocene dichlorides constitute a remarkable class of antineoplastic agents that are highly effective against several cancer cell lines. They were shown to accumulate in the DNA-rich region, which suggests DNA as the primary target. These compounds exhibit two cyclopentadienyl ligands and two labile halide ligands, resulting in a bent sandwich structure. The cis-dihalide motif is structurally related to the cis-chloro configuration of cisplatin and similar modes of action can thus be assumed. Cisplatin binds to two neighboring guanine nucleobases in DNA and consequently, distorts the double-helix, thereby inhibiting DNA replication and transcription. Platinum is classified as a soft Lewis acid and binds preferentially to the nitrogen atoms within the nucleobases. The metallocene dichlorides investigated in this study comprise the metal centers Ti, V, Nb, Mo, Hf, and W, which are classified as hard or intermediate Lewis acids, and thus, favor binding to the phosphate oxygen. Although several studies reported adduct formation of metallocene dichlorides with nucleic acids, substantial information about the adduct composition, the binding pattern, and the nucleobase selectivity has not been provided yet. ESI-MS analyses gave evidence for the formation of metallocene adducts (M = Ti, V, Mo, and W) with single-stranded DNA homologues at pH 7. No adducts were formed with Nb and Hf at neutral pH, albeit adducts with Nb were observed at a low pH. MS2 data revealed considerable differences of the adduct compositions. The product ion spectra of DNA adducts with hard Lewis acids (Ti, V) gave evidence for the loss of metallocene ligands and only moderate backbone fragmentation was observed. By contrast, adducts with intermediate Lewis acids (Mo, W) retained the hydroxy ligands. Preliminary results are in good agreement with the Pearson concept and DFT calculations. Since the metallodrugs were not lost upon CID, the nucleobase selectivity, stoichiometry, and binding patterns can be elucidated by means of tandem mass spectrometry.

Item Type:

Conference or Workshop Item (Poster)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Eberle, Rahel Patricia and Schürch, Stefan

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
600 Technology > 610 Medicine & health

Language:

English

Submitter:

Stefan Schürch

Date Deposited:

02 Feb 2016 16:17

Last Modified:

02 Feb 2016 16:18

URI:

https://boris.unibe.ch/id/eprint/75105

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