Open Access Dissertation
Date of Award
Christine S. Chow
The essential role of ribosomal RNA (rRNA) in the cell life cycle is highlighted by protein synthesis; therefore, the ribosome is considered to be an ideal drug target. Ribosomal RNAs exhibit a high level of structural diversity. The well-known anticancer drug cisplatin was previously applied as a chemical probe of rRNA structure to determine solvent accessible purines (guanosine) in vivo and in vitro. Cisplatin accumulates faster on RNA than DNA, with less chance of repair. As such, designing new RNA-targeting Pt compounds is not only a promising direction for chemical-probing applications, but also for the design of anticancer drugs that could overcome DNA repair-related resistance. In the present study, amino-acid-linked cisplatin analogues were synthesized. Their reactivity and product profiles with RNA were evaluated on the nucleoside level by using high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). Tandem mass spectrometry (MS/MS) combined with computational chemistry was also utilized to assess the effects of Pt(II) on the glycosidic-bond strength of the purine nucleoside, and to obtain an atomic-level understanding of the nucleoside-Pt(II) products. Results reveal a cisplatin analogue with the first-reported template-independent adenosine preference, and demonstrate that Pt(II) reactivity can be tuned by altering the carrier ligand(s). This project also illustrates the potential of MS/MS to be used in RNA-Pt studies and provides details of adduct structures, such as the sites of adduct formation.
Bao, Xun, "Synthesis, Characterization, And Rna Reactivity Of Amino-Acid-Linked Cisplatin Analogues" (2015). Wayne State University Dissertations. 1115.