Gold(III)-Induced Amide\nBond Cleavage In Vivo: A Dual\nRelease Strategy via π‑Acid Mediated Allyl Substitution

Selective cleavage of amide bonds holds prominent significance\nby facilitating precise manipulation of biomolecules, with implications\nspanning from basic research to therapeutic interventions. However,\nachieving selective cleavage of amide bonds via mild synthetic chemistry\nroutes poses a critical challenge. Here, we report a novel amide bond-cleavage\nreaction triggered by Na[AuCl<sub>4</sub>] in mild aqueous conditions,\nwhere a crucial cyclization step leads to the formation of a 5-membered\nring intermediate that rapidly hydrolyses to release the free amine\nin high yields. Notably, the reaction exhibits remarkable site-specificity\nto cleave peptide bonds at the C-terminus of allyl-glycine. The strategic\nintroduction of a leaving group at the allyl position facilitated\na dual-release approach through π-acid catalyzed substitution.\nThis reaction was employed for the targeted release of the cytotoxic\ndrug monomethyl auristatin E in combination with an antibody-drug\nconjugate in cancer cells. Finally, Au-mediated prodrug activation\nwas shown in a colorectal zebrafish xenograft model, leading to a\nsignificant increase in apoptosis and tumor shrinkage. Our findings\nreveal a novel metal-based cleavable reaction expanding the utility\nof Au complexes beyond catalysis to encompass bond-cleavage reactions\nfor cancer therapy.