posted on 2024-03-14, 14:09authored byPaul 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.