Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and <i>N</i>-Propargyl Handles for Drug-Activation
Bruno L. Oliveira, Benjamin J. Stenton, V. Unnikrishnan, Cátia Rebelo de Almeida, João Conde, Magda Negrão, Felipe S. S. Schneider, Carlos Cordeiro, Miguel Godinho Ferreira, Giovanni F. Caramori, Josiel B. Domingos, Rita Fior, Gonçalo J. L. Bernardes
Abstract
-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.