Mitochondria-localizing N-heterocyclic thiosemicarbazone copper complexes with good cytotoxicity and high antimetastatic activity.

Although many N-heterocyclic thiosemicarbazone copper complexes have been proposed as potential anticancer agents, little is known about their intracellular localization in cells. In the present study, we synthesized two fluorescent N-heterocyclic thiosemicarbazone copper complexes, ([CuII(L)(Br)] 1 and [CuII2CuI(L)2(Br)3] 2, where HL is (E)-N,N-dimethyl-2-(quinolin-8-ylmethylene)hydrazinecarbothioamide), to assess their intracellular distribution. Our fluorescence studies demonstrated that complex 1 showed an intense emission band at ca. 510 nm (λex = 405 nm) similar to that of complex 2, albeit with about four times lower emission intensity. Both copper complexes showed significantly greater cytotoxicity toward several tumor cell-types with better IC50 (0.27-0.91 µM) than the HL ligand and cisplatin. Scratching wound healing assay and invasion assay were performed, revealing that the copper complexes have good antimetastatic activity. Confocal fluorescence imaging allowed ascertaining that complex 2 was primarily localized to mitochondria. Further studies revealed that the anticancer mechanisms of complex 2 might involve the mitochondrial-mediated apoptotic pathway, probably caused by the reducing mitochondrial membrane potential and induction of ROS (reactive oxygen species) production. Furthermore, complex 2 exhibited promising cytostatic effects in a three-dimensional HeLa spheroid model.

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]·2H2O 1a, [Cu(L2)Cl]·H2O 2a, and [Cu(L2)NO3]·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]·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)/ligand/co-ligand complex 3b displayed the greatest toxicity toward several cancer cells with better IC50 (1.12-3.77 µM) 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.

Synthesis, structures and urease inhibition studies of Schiff base metal complexes derived from 3,5-dibromosalicylaldehyde.

Eleven mononuclear copper(II), nickel(II), zinc(II) and cobalt(II) complexes of Schiff base ligands derived from 3,5-dibromosalicylaldehyde/3,5-dichlorosalicylaldehyde were synthesized and determined by single crystal X-ray analysis. The crystal structures of complexes 1, 2, 4, 5, 6, 8 and 11 present the square-planar coordination geometry at the metal center and complexes 7, 9 and 10 show the distorted tetrahedral geometry. While one copper center in 3 has a square-planar geometry, the other copper is slightly distorted square-planar. The inhibitory activities of all the obtained complexes were tested in vitro against jack bean urease. It was found that Schiff base copper(II) complexes 1, 3, 5, 8 and 11 showed strong urease inhibitory activities (IC(50) = 1.51-3.52 µM) compared with acetohydroxamic acid (IC(50) = 62.52 µM), which was a positive reference. Their structure-activity relationships were further discussed.

Synthesis, structures and urease inhibition studies of copper(II) and nickel(II) complexes with bidentate N,O-donor Schiff base ligands.

Five mononuclear copper(II) and nickel(II) complexes of Schiff base ligands derived from 4-hydroxyphenethylamine and 2-phenylethylamine were synthesized and determined by single crystal X-ray analysis. The crystal structures of these complexes presented the square planar coordination geometry at the metal center. The inhibitory activity of all the obtained complexes was tested in vitro against jack bean urease. It was found that Schiff base copper(II) complexes, namely [Cu(C(15)H(13)BrNO(2))(2)]·2(C(6)H(7)N) (1), [Cu(C(15)H(12)Br(2)NO(2))(2)]·2(DMF) (2), Cu(C(19)H(16)NO(2))(2) (3) and Cu(C(19)H(16)NO)(2) (5), showed strong inhibitory activity against jack bean urease (IC(50)=1.45-3.59 µM), while Schiff base nickel(II) complex, [Ni(C(19)H(16)NO(2))(2)]·2(DMF) (4), exhibited weak inhibitory activity (IC(50)>50 µM). Their structure-activity relationships were further discussed.