Deciphering the Cellular Behavior of Organoruthenium(II)-Pyrithionato Complexes in Ovarian Cancers

Abstract Ovarian cancer remains a significant societal burden. Innovations in treatment are limited, and chemotherapy still relies heavily on platinum drugs. This is especially relevant for patients who develop Pt-resistant recurrences. Organoruthenium-arene complexes have shown considerable promise in overcoming this limitation and may be developed as viable alternatives. We focused on understanding the effects of fluoro- and cyano-substitutions (R) on pyrithione(pth) ligands in new complexes with the general formula [Ru(η6-p-cymene)(pth-R)Cl] or [Ru(η6-p-cymene)(pth-R)(L)]PF6, particularly regarding their position on the aromatic ring. We investigated the contrasting cellular behavior between complexes with chlorido, triphenylphosphite [P(OPh)3] and triphenylphosphine [PPh3] as monodentate ligands (L). The PPh3-derived complex demonstrated significant anticancer activity, limiting proliferation, migration, and aggregation of A2780 cells. The phosphorus-containing complexes disrupted cellular membrane integrity, altered mitochondrial membrane potential, increased ROS production, and induced irregular nuclear morphology consistent with DNA packaging alterations. They induced late apoptosis and G2 cell cycle arrest. No significant non-apoptotic alternative mechanisms of cell death have been identified.