Abstract

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,20:60,200-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(II )-based monofunctional agents. Notably, the extension of the terpyridine at the 40 position with an aromatic ring resulted in a molecule that was cytotoxic in several cancer cell lines with sub-micromolar IC50 values, induced ribosome biogenesis stress, and exhibited minimal zebrafish embryo toxicity. This study demonstrates the successful design of a Ru(II ) agent that mimics many of the biological effects and phenotypes seen with phenanthriplatin, despite numerous differences in both the ligands and metal center structure.

Document Type

Article

Publication Date

2023

Notes/Citation Information

© 2023 The Author(s). Published by the Royal Society of Chemistry

Digital Object Identifier (DOI)

https://doi.org/10.1039/d2cb00247g

Funding Information

We gratefully acknowledge the National Institutes of Health (Grant GM107586) and the National Science Foundation (Grant MCB-1453168) for the support of this research. We also acknowledge the University of Kentucky Light Microscopy Core, which is supported in part by the Office of the Vice President for Research. We are profoundly thankful to Professor Richard Wood’s lab for allowing us to use their HeLa XPA knockout cell line. This research was also supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558).

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