Catalytic Glutathione Oxidation and Platinum(IV) Prodrug Activation via a Ruthenium-Flavin Catalyst

Abstract

Cyclopentadienyl (Cp) Ru(IV) quinoline complexes are known for their role in bioorthogonal catalysis within cellular environments, where they use endogenous GSH to deprotect profluorescent and prodrug substrates. However, their reactivity toward GSH and potential for redox-mediated therapies remain underexplored. This study presents RuQ-TARF, a Cp-Ru(IV) complex with a quinoline ligand linked to 2′,3′,4′,5′-tetraacetylriboflavin (TARF) as a redox-active moiety. Its catalytic activity in oxidizing GSH and activating a Pt(IV) prodrug of oxaliplatin was investigated. RuQ-TARF catalyzes the oxidation of GSH to GSSG, improving electron transfer compared to RuQ, its flavin-free analogue. LC–MS analysis showed that activating the Pt(IV) prodrug with GSH produces multinuclear Pt(II)-GS species. RuQ-TARF was additionally evaluated during coincubation with GSH and NADH under blue light, where NADH enabled faster activation of the prodrug, producing oxaliplatin as confirmed by ¹H and ¹⁹⁵Pt NMR. Cyclic voltammetry showed that linking TARF to RuQ improves the reversibility of redox processes, enhancing catalytic performance and supporting its use in combined GSH oxidation and prodrug activation strategies.