A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin. Academic Article uri icon

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.

published proceedings

  • RSC Chem Biol

altmetric score

  • 15.95

author list (cited authors)

  • Mitchell, R. J., Kriger, S. M., Fenton, A. D., Havrylyuk, D., Pandeya, A., Sun, Y., ... Glazer, E. C.

citation count

  • 0

complete list of authors

  • Mitchell, Richard J||Kriger, Sarah M||Fenton, Alexander D||Havrylyuk, Dmytro||Pandeya, Ankit||Sun, Yang||Smith, Tami||DeRouchey, Jason E||Unrine, Jason M||Oza, Viral||Blackburn, Jessica S||Wei, Yinan||Heidary, David K||Glazer, Edith C

publication date

  • May 2023