University of Limerick
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Click-capable phenanthriplatin derivatives as tools to study Pt(II)- induced nucleolar stress

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journal contribution
posted on 2024-05-13, 10:50 authored by Paul D. O’Dowd, Andres S. Guerrero, Katelyn R. Alley, Hannah C. Pigg, Fiona O’Neill, Justine Meiller, Chloe Hobbs, Daniel A. Rodrigues, Brendan Twamley, Finbarr O’Sullivan, Victoria J. DeRose, Darren M Griffith

It is well established that oxaliplatin, one of the three Pt(II) anticancer drugs approved worldwide, and phenanthriplatin, an important preclinical monofunctional Pt(II) anticancer drug, possess a different mode of action from that of cisplatin and carboplatin, namely, the induction of nucleolar stress. The exact mechanisms that lead to Pt-induced nucleolar stress are, however, still poorly understood. As such, studies aimed at better understanding the biological targets of both oxaliplatin and phenanthriplatin are urgently needed to expand our understanding of Pt-induced nucleolar stress and guide the future design of Pt chemotherapeutics. One approach that has seen great success in the past is the use of Pt-click complexes to study the biological targets of Pt drugs. Herein, we report the synthesis and characterization of the first examples of click-capable phenanthriplatin complexes. Furthermore, through monitoring the relocalization of nucleolar proteins, RNA transcription levels, and DNA damage repair biomarker γH2AX, and by investigating their in vitro cytotoxicity, we show that these complexes successfully mimic the cellular responses observed for phenanthriplatin treatment in the same experiments. The click-capable phenanthriplatin derivatives described here expand the existing library of Pt-click complexes. Significantly they are suitable for studying nucleolar stress mechanisms and further elucidating the biological targets of Pt complexes.


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ACS Chemical Biology, 2024, 19, (4), pp. 875-885


American Chemical Society

Other Funding information

DMG, POD and FOS gratefully acknowledge funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under [grant number 12/RC/2275_P2].This work was supported by the National Science Foundation [CHE2109255 to V. J. D., NSF DGE-2022168 to ASG and KRA]. This work is also supported by the Department of Chemistry and Biochemistry and the Material Science Institute at the University of Oregon.

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