Riboflavin acts as bioorthogonal photocatalyst to activate a PtIV anticancer prodrug in the biological environment.

Catalytic reactions that use metal complexes as substrates, rather than catalysts, are nearly unknown. We recently demonstrated that certain flavins (FLs) are potent redox photocatalysts capable of converting Pt IV anticancer prodrug complexes into Pt II drugs in the biological environment. Herein, we investigate the mechanism of these artificial photocatalytic reactions employing four different free flavins, namely riboflavin (Rf), flavin mononucleotide (FMN), tetra-O-acetyl riboflavin (TARF) and lumiflavin (Lf), and the flavoprotein miniSOG (mini Singlet Oxygen Generator) together with a panel of Pt IV substrates conveniently selected. NMR, steady-state and time-resolved optical spectroscopy studies highlight that light activation of FLs in the presence of NADH as electron donor (pH 7-7.5) eventually leads to the generation of the reduced FLHspecies which catalyzes the Pt IV -to-Pt II conversion with turnover frequency (TOF) values ranging between 1.3 and 30 min -1 , and turnover number (TON) values reaching 500. Comparable catalytic efficiency is also found for reactions performed in cell culture medium. Density functional theory suggests that activation via reduction of the Pt IV complexes may be influenced by H-bonding interactions between the FL catalyst and the metal substrate and confirm that both the isoalloxazine Page 1 of 25 ACS Paragon Plus Environment ACS Catalysisand ribityl moieties of the FLs determine the catalytic efficiency of the process. The FMNcontaining miniSOG is a less effective catalyst (TOFs < 5.6 min -1 ) since the formation of the doubly reduced FMNHcompetes with an electron transfer reaction involving the protein matrix which quenches the FMN excited state to give a singly-reduced FMN •-.

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