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Glutathione (GSH) is a critical compound as it is highly concentrated intracellularly and can reduce and dissociate copper(II) from the ligand forming poorly redox\u2010active copper(I)\u2010thiolate clusters. Here we report that Cu\u2010Phen\n                    <jats:sub>2<\/jats:sub>\n                    speciation evolves in physiologically relevant GSH concentrations. Experimental and computational experiments suggest that at pH\u00a07.4 mostly copper(I)\u2010GSH clusters are formed, but a minor species of copper(I) bound to one Phen and forming ternary complexes with GSH (GS\u2212Cu\u2010Phen) is the redox active species, oxidizing quite efficiently GSH to GSSG and forming HO\u22c5 radicals. This minor active species becomes more populated at lower pH, such as typical lysosomal pH\u00a05, resulting in faster GSH oxidation and HO\u22c5 production. Consistently, cell culture studies showed lower toxicity of Cu\u2010Phen\n                    <jats:sub>2<\/jats:sub>\n                    upon inhibition of lysosomal acidification. Overall, this study underscores that sub\u2010cellular localisation can considerably influence the speciation of Cu\u2010based drugs and that minor species can be the most redox\u2010 and biologically\u2010active.\n                  <\/jats:p>","DOI":"10.1002\/anie.202414652","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T03:08:05Z","timestamp":1728011285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["When Metal Complexes Evolve, and a Minor Species is the Most Active: the Case of Bis(Phenanthroline)Copper in the Catalysis of Glutathione Oxidation and Hydroxyl Radical Generation"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1944-3552","authenticated-orcid":false,"given":"Enrico","family":"Falcone","sequence":"first","affiliation":[{"name":"Institut de Chimie (UMR 7177) University of Strasbourg, CNRS  4 Rue Blaise Pascal 67081 Strasbourg France"},{"name":"current address: Laboratoire de Chimie de Coordination (UPR 8142) CNRS  31077 Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Vigna","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Technologies Universit\u00e0 della Calabria  87036 Arcavacata di Rende CS Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemma","family":"Schueffl","sequence":"additional","affiliation":[{"name":"Center for Cancer Research and Comprehensive Cancer Center Medical University of Vienna  1090 Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8102-7982","authenticated-orcid":false,"given":"Francesco","family":"Stellato","sequence":"additional","affiliation":[{"name":"Department of Physics Universit\u00e0 di Roma Tor Vergata  Via della Ricerca Scientifica 1 00133 Roma Italy"},{"name":"INFN Universit\u00e0 di Roma Tor Vergata  Via della Ricerca Scientifica 1 00133 Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7527-2068","authenticated-orcid":false,"given":"Bertrand","family":"Vileno","sequence":"additional","affiliation":[{"name":"Institut de Chimie (UMR 7177) University of Strasbourg, CNRS  4 Rue Blaise Pascal 67081 Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merwan","family":"Bouraguba","sequence":"additional","affiliation":[{"name":"Institut de Chimie (UMR 7177) University of Strasbourg, CNRS  4 Rue Blaise Pascal 67081 Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Mazzone","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Technologies Universit\u00e0 della Calabria  87036 Arcavacata di Rende CS 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