Riboflavin as a bioorthogonal photocatalyst for the activation of a PtIV prodrug

Encouraging developments demonstrate that few transition metal and organometallic catalysts can operate in a bioorthogonal fashion and promote non-natural chemistry in living systems by minimizing undesired side reactions with cellular components. These catalytic processes have potential for applications in medicinal chemistry and chemical biology. However, the stringent conditions of the cell environment severely limit the number of accessible metal catalysts and exogenous reactions. Herein, we report an unorthodox approach and a new type of bioorthogonal catalytic reaction, in which a metal complex is an unconventional substrate and an exogenous biological molecule acts as a catalyst. In this reaction, riboflavin photocatalytically converts a PtIV prodrug into cisplatin within the biological environment. Due to the catalytic activity of riboflavin, cisplatin-like apoptosis is induced in cancer cells under extremely low doses of light, potentially preventing systemic off-target reactions. Photocatalytic and bioorthogonal turnover of PtIV into PtII species is an attractive strategy to amplify the antineoplastic action of metal-based chemotherapeutics with spatio-temporal control.This work was supported by the Spanish Ministry of Economy and Competitiveness (grant CTQ2016-80844-R, BES-2013-065642, BIO2014-61838-EXP and BIO2015-69887-R), the Department of Industry of the Basque Country (grant ETORTEK). L. S. thanks the MICINN of Spain for the Ramón y Cajal Fellowship RYC-2011-07787 and the MC CIG fellowship UCnanomat4iPACT (grant no. 321791). L. S., F. L. G. and J. M. R. thank Ikerbasque for funding. We are also grateful to the members of the European COST Actions CM1105, CM103 and CM1403 for stimulating discussions