Novel Mixed-Ligand Copper(I) Complexes: Role of Diimine Ligands on Cytotoxicity and Genotoxicity
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- 作者：Valentina Gandin ; Marina Porchia ; Francesco Tisato ; Alessandro Zanella ; Emilia Severin ; Alessandro Dolmella ; Cristina Marzano
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：September 26, 2013
- 年：2013
- 卷：56
- 期：18
- 页码：7416-7430
- 全文大小：522K
- 年卷期：v.56,no.18(September 26, 2013)
- ISSN：1520-4804
文摘
Novel tetrahedral copper(I) mixed-ligand complexes of the type [Cu(X)(N鈭?/sup>N)(PCN)], 3鈥?b>10, where X = Cl or Br, N鈭?/sup>N = 2,2鈥?bipyridine (bipy), 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline (dmp), and dipyrido-[3,2-d:2鈥?3鈥?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)]路DMF (5路DMF) and [CuBr(dpq)(PCN)]路2DMF (10路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.