biostudies-literatureOchs JDeutsche Forschungsgemeinschaft4183-4190https://www.ebi.ac.uk/biostudies/studies/S-EPMC12777740biostudies-literatureUnknown17(8)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 sChemical scienceIdentification of Au-hydrides as key intermediates in the reduction of Au(iii) prodrugs to active Au(i) species under protic conditions.PMC12777740GRK 2341 “Microbial Substrate Conversion”Metzler-Nolte NOchs JfalseIdentification of Au-hydrides as key intermediates in the reduction of Au(iii) prodrugs to active Au(i) 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 s2026-01-01T00:00:00Z2026 Feb2026-07-16T21:26:13.256Z2026-07-10T03:16:03.167ZS-EPMC127777404151001310.1039/d5sc06212h