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)(OH(2))(2)(OClO(3))(2), and determined the complex formation constants of [Cu(phen)(L)](2+). We studied the cytotoxic activity of [Cu(phen)(2)(L)](ClO(4))(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.
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, 09042 Monserrato (CA), Italy. tpivetta@unica.it
Tiziana
T
Pivetta
Francesco
F
Isaia
Gaetano
G
Verani
Carla
C
Cannas
Laura
L
Serra
Carlo
C
Castellano
Francesco
F
Demartin
Federica
F
Pilla
Matteo
M
Manca
Alessandra
A
Pani
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005031:Ethylenethiourea; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000737:chemistry*; D013871:Thiones / Q000737:chemistry
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D048289:Imidazolidines; D010618:Phenanthrolines; D013871:Thiones; D005031:Ethylenethiourea; D003300:Copper; D005978:Glutathione; C025205:1,10-phenanthroline