title: Novel mixed-ligand copper(I) complexes: role of diimine ligands on cytotoxicity and genotoxicity.
abstract: Novel tetrahedral copper(I) mixed-ligand complexes of the type [Cu(X)(N(∩)N)(PCN)], 3-10, where X = Cl or Br, N(∩)N = 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline (dmp), and dipyrido-[3,2-d:2',3'-f]-quinoxaline (dpq), and PCN = tris-(2-cyanoethyl)phosphine, have been synthetized and characterized by NMR, ESI-MS, and X-ray diffraction on two representative examples, [CuCl(phen)(PCN)]·DMF (5·DMF) and [CuBr(dpq)(PCN)]·2DMF (10·2DMF). Cu(I) complexes were evaluated for their in vitro antitumor properties against a panel of human cancer cell lines, including cisplatin- and multidrug-resistant sublines. The most effective complex, [CuCl(dpq)(PCN)] (9), exhibited nanomolar cytotoxicity toward both sensitive and resistant cancer cells, but it significantly inhibited the growth of cultured normal cells. In vitro DNA assays and single cell gel electrophoresis revealed that 9 induced DNA fragmentation resulting in cell apoptosis. In parallel, fluorescence in situ hybridization (FISH) micronucleus assay attested high levels of genotoxicity following treatment of peripheral blood lymphocytes with complex 9, suggesting that the potential risk posed by diimine metal complexes should be carefully reconsidered.
authors: Dipartimento di Scienze del Farmaco, Università di Padova , via Marzolo 5, 35131 Padova, Italy.
authors: Valentina
authors: V
authors: Gandin
authors: Marina
authors: M
authors: Porchia
authors: Francesco
authors: F
authors: Tisato
authors: Alessandro
authors: A
authors: Zanella
authors: Emilia
authors: E
authors: Severin
authors: Alessandro
authors: A
authors: Dolmella
authors: Cristina
authors: C
authors: Marzano
mesh_terms: D024422:Aneugens / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D007097:Imines / Q000737:chemistry*; D008024:Ligands; D015162:Micronucleus Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D024422:Aneugens; D000970:Antineoplastic Agents; D007097:Imines; D008024:Ligands; D009942:Organometallic Compounds; D003300:Copper; D004247:DNA