Identification of Au-hydrides as key intermediates in the reduction of Au( <scp>iii</scp> ) prodrugs to active Au( <scp>i</scp> ) species under protic conditions

Similar to Pt^IV prodrugs, Au^III anticancer complexes are believed to undergo intracellular reduction, thereby gaining their activity from the resulting Au^I species. Unlike for Pt^IV, the underlying mechanism of this process remains poorly understood for Au^III. To elucidate this mechanism, we investigated the reaction of [Au(ppy)Cl₂], a model Au^III complex (ppy: phenylpyridine), with two biologically relevant reductants: lipoic acid (lpa) and <i>N</i>-acetyl-l-cysteine-methyl ester (NAC-OMe). Our findings reveal that lpa transfers a hydride to the Au, while cysteine derivatives only bind to the metal. The Au-H complex, even visible in protic solvents by NMR spectroscopy, produced by lpa is essential for enabling a sequence of oxidative addition and reductive elimination reactions that lead to Au^I species eventually. These observations provide valuable insights into the mechanisms by which anticancer gold drug candidates are reduced within the cell.