Mixed-ligand Cu(II) hydrazone complexes designed to enhance anticancer activity

The ligand quantity, ligand type, and coordination geometry have important influences on the anticancer activity of metal-based complexes. On the basis of the structures of previously reported 1:1 Cu(II)/ligand complexes ([Cu(L1)Cl]center dot 2H(2)O la, [Cu(L2)Cl]center dot H2O 2a, and [Cu(L2)NO3]center dot H2O 3a), we subsequently designed, developed, and characterized a series of corresponding 1:1:1 Cu(II)/ligand/co-ligand complexes ([Cu(L1)(PY)Cl]center dot H2O 1b, [Cu(L2)(PY)Cl] 2b, and [Cu(L2)(PY)NO3] 3b), where L1 = (E)-N'-(2-hydroxybenzylidene)acetohydrazide, L2 = (E)-N'-(2-hydroxybenzylidene)benzohydrazide, and Py = pyridine. All six Cu(II) complexes were assessed for their in vitro anticancer properties against a panel of human cancer cells, including cisplatin-resistant A549cisR cell lines. Interestingly, we observed that the 1:1:1 Cu/ligand/co-ligand mixed-ligand Cu(II) complexes exhibited higher anticancer activity than the corresponding 1:1 Cu(II)/ligand complexes. In particular, the 1:1:1 Cu(II)/ligandico-ligand complex 3b displayed the greatest toxicity toward several cancer cells with better IC50 (1.12-3.77 mu M) than cisplatin. Further mechanistic explorations showed that the 3b complex induced DNA damage, thus resulting in mitochondria-mediated apoptotic cell death. Furthermore, the 3b complex displayed pronounced cytostatic effects in the MCF-7 3D spheroid model. (C) 2018 Elsevier Masson SAS. All rights reserved.