Mixed-1,10-phenanthroline–Cu(II) complexes: Synthesis, cytotoxic activity versus hematological and solid tumor cells and complex formation equilibria with glutathione

Cu(II) complexes with 1,10-orthophenanthroline (phen) show cytotoxic and antitumoral effects. To enhance and exploit these features, we studied complexes containing one or two phen units together with N,N′-substituted-imidazolidine-2-thione (L). We synthesized and structurally characterized the precursor molecule Cu(phen)(OH2)2(OClO3)2, and determined the complex formation constants of [Cu(phen)(L)]2+. We studied the cytotoxic activity of [Cu(phen)2(L)](ClO4)2 versus human hematologic (CCRF-CEM and CCRF-SB) and solid tumor-derived cell lines (K-MES-1, DU-145). The cytotoxic activities, in the 1–3 μM range, show that our Cu(II)–complexes possess comparable inhibitory activities against both leukemia and carcinoma cells, unlike the majority of antineoplastic agents, usually more potent against hematologic cancer cells than against solid tumor cells. Because the free Cu(II) ion is reduced by glutathione (GSH), we studied the reactivity of our complexes with GSH, providing evidence that no redox reaction occurred under the chosen experimental conditions. Complex formation equilibria were present, studied by spectrophotometric titrations. The redox properties of the prepared compounds were also investigated by cyclic voltammetry, confirming that the mixed Cu(II) complexes were resistant to reduction.

Graphical abstractCu(II) complexes with 1,10-orthophenanthroline (phen) show antitumoral effects. We synthesized mixed Cu(II)–phen complexes with inhibitory activities against leukemia and carcinoma cells. The redox properties of the compounds and the reactivity with glutathione were investigated. In the pictogram the cyclic voltammograms of [Cu(phen)(OH2)]2+ (―), [Cu(phen)2(OH2)]2+ (-■-) and [Cu(phen)2(L1)]2+ (-□-) are reported.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Cytotoxic and antitumoral effects of Cu(II)–1,10-phenanthroline compounds. ► Inhibitory activities on leukemia and carcinoma cells. ► Crystal structure of Cu(1,10-phenanthroline)2(OH2)2(OClO3)2 ► Solution equilibria study of mixed Cu(II) complexes and glutathione