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We have developed a series of Cu<jats:sup>II<\/jats:sup> complexes with tridentate pyridine aminophenolate\u2010based ligands for preferential activation in the reduction window provided by hypoxic tissues. Furthermore, ligand functionalization with a pendant CF<jats:sub>3<\/jats:sub> group provides a <jats:sup>19<\/jats:sup>F spectroscopic handle for magnetic\u2010resonance studies of redox processes at the metal centre and behaviour in cellular environments. The phenol group in the ligand backbone was substituted at the <jats:italic>para<\/jats:italic> position with H, Cl, and NO<jats:sub>2<\/jats:sub> to modulate the reduction potential of the Cu<jats:sup>II<\/jats:sup> centre, giving a range of values below the window expected for hypoxic tissues. The NO<jats:sub>2<\/jats:sub>\u2010substituted complex, which has the highest reduction potential, showed enhanced cytotoxic selectivity towards HeLa cells grown under hypoxic conditions. Cell death occurs by apoptosis, as determined by analysis of the cell morphology. A combination of <jats:sup>19<\/jats:sup>F NMR and ICP\u2010OES indicates localization of the NO<jats:sub>2<\/jats:sub> complex in HeLa cell nuclei and increased cellular accumulation under hypoxia. This correlates with DNA nuclease activity being the likely origin of cytotoxic activity, as demonstrated by cleavage of DNA plasmids in the presence of the Cu<jats:sup>II<\/jats:sup> nitro complex and a reducing agent. Selective detection of the paramagnetic Cu<jats:sup>II<\/jats:sup> complexes and their diamagnetic ligands by <jats:sup>19<\/jats:sup>F MRI suggests hypoxia\u2010targeting theranostic applications by redox activation.<\/jats:p>","DOI":"10.1002\/chem.202100603","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T14:34:35Z","timestamp":1619015675000},"page":"9839-9849","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Copper(II) Pyridyl Aminophenolates: Hypoxia\u2010Selective, Nucleus\u2010Targeting Cytotoxins, and Magnetic Resonance Probes"],"prefix":"10.1002","volume":"27","author":[{"given":"Kathleen E.","family":"Prosser","sequence":"first","affiliation":[{"name":"Department of Chemistry Simon Fraser University  8888 University Dr. Burnaby BC V5A 1S6 Canada"},{"name":"Department of Chemistry The University of Texas at Austin  105 E. 24th Street Stop A5300 Austin TX 78712 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