Flavin Bioorthogonal Photocatalysis Toward Platinum Substrates

Abstract

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 •-.

Transfer hydrogenation catalysis in cells

“…51 We discuss these recent developments including detailed mechanisms of action, along with recent work on in-cell photo-catalytic reduction of metal complexes by flavines. 20,[52][53][54][55] Coenzymes NAD + /NADH play important roles in maintaining the intracellular redox balance and mitochondrial electron transport chain, and such in-cell transfer hydrogenation catalysts might find application in biotechnology and therapy, for example as catalytic anticancer drugs.…”

Toward supramolecular nanozymes for the photocatalytic activation of Pt(iv) anticancer prodrugs

“…1A) which is the active catalyst prompting the bioorthogonal substrate conversion. 11,13 In vitro experiments also demonstrated that this activation strategy hold promise for its capacity to deliver lethal concentrations of Pt drugs with minimal light doses. 11,16 The relevance of Pt(IV) complexes in photochemotherapy research is proved by the numerous photoactivatable prodrugs and activation approaches developed in recent years.…”

“…As previously reported, FMN alone cannot catalytically reduce 1 in the absence of light, nor under light irradiation without electron donor. 13 Controls showed that TACN AuNPs only prompted a 15% substrate conversion in the dark, both with and without FMN loaded ( Fig. S7 and S8, ESI †).…”

“…1A). [11][12][13] As rarely observed in catalysis, 14,15 metal complexes act as substrates rather than catalysts in these unconventional processes. Mechanistic studies highlighted that light excitation of flavins in the presence of an electron donor (e.g.…”

Enhancing The Photocatalytic Conversion Of Pt(IV) Substrates By Flavoprotein Engineering

“…(a) General photocatalytic mechanism for the Pt(IV) prodrug activation by flavins; R1 = e.g. ribityl, ribityl phosphate, R2 = adenosine diphosphate ribose and R3 = CH2CH2COOH (1) or CH3 (2). (b) mSOG's molecular model based on the structure of iLOV protein (PBD ID: 6GPU).…”