Bioorthogonal Catalytic Activation of Platinum and Ruthenium Anticancer Complexes by FAD and Flavoproteins

Abstract

Recent advances in bioorthogonal catalysis promise to deliver new chemical tools for performing chemoselective transformations in complex biological environments. Herein, we report how FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), and four flavoproteins act as unconventional photocatalysts capable of converting PtIV and RuII complexes into potentially toxic PtII or RuII−OH2 species. In the presence of electron donors and low doses of visible light, the flavoproteins mini singlet oxygen generator (miniSOG) and NADH oxidase (NOX) catalytically activate PtIV prodrugs with bioorthogonal selectivity. In the presence of NADH, NOX catalyzes PtIV activation in the dark as well, indicating for the first time that flavoenzymes may contribute to initiating the activity of PtIV chemotherapeutic agents.

Biological activity of PtIV prodrugs triggered by riboflavin-mediated bioorthogonal photocatalysis

“…In our search for novel activation strategies, we recently showed that Rf and other flavins, including flavoproteins, can simultaneously act as photosensitizers and unconventional photocatalysts for the selective activation of anticancer metal-based prodrug candidates such as Pt IV complexes. These photocatalytic reactions efficiently deliver active Pt II species and take place by means of blue rather than UV-A light in the presence of zwitterionic buffers such as MES (2-(N-morpholino)ethanesulfonic acid), as well as with biological electron donors such as NAD(P)H 10 , 11 . Importantly, low doses of blue light are sufficient to fully convert high concentrations of Pt IV prodrugs in buffer solution and in cell culture medium.…”

“…Importantly, low doses of blue light are sufficient to fully convert high concentrations of Pt IV prodrugs in buffer solution and in cell culture medium. The Rf selectivity for Pt IV complexes demonstrated in the biological environment defines the bioorthogonal nature of these photocatalytic reactions 10 , 11 . According to our current understanding of the process (Fig.…”

Nature is the Cure: Engineering Natural Redox Cofactors for Biomimetic and Bioinspired Catalysis

“…Recently, an exciting prospect for flavins has been reported and shows that such derivatives can be used as efficient pro‐drug activators. Upon light‐activation, a flavin can be used as a catalyst to transform a metallo‐prodrug into its active species (Scheme ) . This flavin‐mediated bioorthogonal catalytic photoactivation of anti‐cancer metal complexes relies on a 2 electrons reduction of the flavin, along with a photooxidation of electron‐donor molecules.…”

“…Upon light-activation, a flavin can be used as a catalyst to transform a metallo-prodrug into its active species (Scheme 8). [62,63,64] This flavin-mediated bioorthogonal catalytic photoactivation of anti-cancer metal complexes relies on a 2 electrons reduction of the flavin, along with a photooxidation of electron-donor molecules. This doubly reduced flavin can then react and transfer electrons to a metal-based prodrug and catalytically generate in situ the actual metal-based drug needed for therapeutic action.…”

Functional Characterization and Structural Analysis of NADH Oxidase Mutants from Thermus thermophilus HB27: Role of Residues 166, 174, and 194 in the Catalytic Properties and Thermostability

“…Tt-NOX presents high chemical and thermal stability, broad-range pH activity, and it can accept NADH or NADPH as substrates [3,10]. Thus, Tt-NOX has successfully been applied to cofactor regeneration systems in the kinetic resolution of secondary alcohols [10] and the selective oxidation of glycerol to yield 1,3-dihydroxyacetone [11,12], in the in situ production of H 2 O 2 coupled to immobilized preparation of peroxidase from horseradish to oxidize pollutants in aqueous solutions [13], in the activation of Pt IV and Ru II chemotherapeutic agents [14], and in biosensors [15,16,17,18,19,20].…”