New cyclometalated Ru(ii) polypyridyl photosensitizers trigger oncosis in cancer cells by inducing damage to cellular membranes

Abstract

A new generation series of cyclometalated Ru(II) polypyridyl complexes of the type [Ru(C^N)(N^N)₂]⁺, Ru1–Ru4, were rationally designed and synthesized, where N^N = 2,2′-bipyridine (bpy) and dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq) and C^N = deprotonated methyl 1-butyl-2-aryl-benzimidazolecarboxylate with p-CF₃C₆H₄ or p-Me₂NC₆H₄ substituents in the R₃ position of the phenyl ring. The photophysical properties of Ru1–Ru4 revealed absorption maxima around 560 nm with an absorption up to 700 nm. The new Ru complexes were able to generate singlet oxygen (¹O₂) upon green light irradiation in acetonitrile, with complexes containing the CF₃ group, Ru1 and Ru3, being the best performers. Furthermore, Ru1 and Ru3 were also able to photogenerate hydroxyl radicals OH˙. By having PSs capable of undergoing both type I and type II mechanisms, a broader range of cytotoxic effects is achieved. Ru1–Ru4 accumulated in membrane-rich compartments, including the cytoplasmic membrane, mitochondria, and endoplasmic reticulum in HeLa cells. Upon irradiation of Ru1 with green light, all these compartments were damaged in treated cells. Based on in vitro experiments, we deduced that the compound Ru1 under irradiation has the capability to disrupt phospholipid membranes directly. Additionally, differential scanning calorimetry of living cells also indicated damage of cytoplasmic/membrane proteins, ultimately leading to cell death via oncosis.