As major players in translation and the cell life cycle, ribosomal RNAs (rRNAs) exhibit a high level of structural diversity. The anticancer drug cisplatin has been applied as a chemical probe to determine solvent and structural accessibility of guanosine sites on rRNAs. Aquated cisplatin has been shown to accumulate faster on RNA than DNA, and Pt(II) adducts are retained on rRNA at a variety of sites. The goal of our work was to design new RNA-targeting platinum(II) compounds for chemical probing applications, as well as the development of anticancer drugs that could potentially overcome DNA repair-related resistance. In this study, amino-acid-linked platinum(II) analogues were synthesized. Their reactivity and product profiles were evaluated on the nucleoside level by using high performance liquid chromatography and nuclear magnetic resonance spectroscopy. Tandem mass spectrometry was used to assess the effects of Pt(II)-adduct formation on glycosidic bond strength and to obtain an atomic-level understanding of the nucleoside-Pt(II) products. These results reveal a cisplatin analogue with a template-independent adenosine preference, and demonstrate that Pt(II) reactivity can be tuned by altering the carrier ligand(s).

Formation and characterization of platinum adducts on ribosomal RNA

249th National Meeting (2015)

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