Issue 5, 2023

A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin

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 = 2,2′:6′,2′′-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 4′ 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.

Graphical abstract: A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin

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Article information

Article type
Paper
Submitted
18 dez 2022
Accepted
01 fev 2023
First published
27 fev 2023
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2023,4, 344-353

A monoadduct generating Ru(II) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin

R. J. Mitchell, S. M. Kriger, A. D. Fenton, D. Havrylyuk, A. Pandeya, Y. Sun, T. Smith, J. E. DeRouchey, J. M. Unrine, V. Oza, J. S. Blackburn, Y. Wei, D. K. Heidary and E. C. Glazer, RSC Chem. Biol., 2023, 4, 344 DOI: 10.1039/D2CB00247G

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