Anticancer activity of Ni(II) and Zn(II) complexes based on new unsymmetrical salophen-type ligands: synthesis, characterization and single-crystal X-ray diffraction.

The discovery of new coordination compounds with anticancer properties is an active field of research due to the severe side effects of platinum-based compounds currently used in chemotherapy. In the search for new agents for the treatment of cancer, unsymmetrical N2O2-tetradentate ligand (H2L1 and H2L2) and their Ni(II) and Zn(II) asymmetric complexes (NiII-L1-2 and ZnII-L1-2) have been synthesized and fully characterized. 1H NMR studies revealed that the ligands and complexes were stable in mixtures of DMSO : D2O (9 : 1). Complementary UV-Vis studies confirmed that ZnII derivatives also exhibit high stability in mixtures DMSO : buffer (6 : 4) after 24 h. Single-crystal X-ray diffraction studies confirmed the molecular structures of H2L1, H2L2, NiII-L1, and NiII-L2. At the molecular level, complexes were completely planar without significant distortions of the square-planar geometry according to τ4 parameter. Furthermore, the crystalline structures revealed non-classical intermolecular interactions of the C-H⋯O and the Ni⋯Ni type. The ligands and complexes were screened against the human osteosarcoma (MG-63), human colon cancer (HCT-116), breast cancer (MDA-MB-231) cell lines, and non-cancerous cells (L929). H2L1 and H2L2 ligands not caused cytotoxic effects at a concentration of 100 µM, while NiII-L2, ZnII-L1, and ZnII-L2 complexes induce cytotoxic effects in all cell lines. NiII-L2 was a more active complex against MG-63 (3.9 ± 1.5) and HCT-116 (3.4 ± 1.7) cell lines with IC50 values in the low micromolar range. In addition, this compound was 10-, 5-, and 11-fold more potent than cisplatin in MG-63 (39 ± 1.8), HCT-116 (17.2), and MDA-MB-231 (131 ± 18), respectively. Three complexes exhibited great selectivity for tumoral cells with SI values ranging from 1.6 to 7.4.

Antiproliferative activity of two copper (II) complexes on colorectal cancer cell models: Impact on ROS production, apoptosis induction and NF-κB inhibition.

The main goal of this work was to screen the antiproliferative activity and mechanism of actions of two copper complexes: [Cu(dmp)2(CH3CN)]2+ (1) and [Cu(phen)2(CH3CN)]2+ (2) on 2D and 3D colorectal cancer cells models. Cell viability studies on three colorectal cancer cell lines (HT-29, LS174T, Caco-2) displayed that 1 showed more robust antiproliferative activity than 2 and cisplatin. Intracellular copper content (63.24% and 48.06% for 1 and 2, respectively) can explain the differences in the cytotoxicity assay. ROS production is the primary mechanism of action involved in the antiproliferative activity of 1 showing 4-, 70- and 2.5- fold increased values of ROS level for HT-29, LS174T, Caco-2 cancer cell lines, respectively. This effect takes place along with the depolarization of the mitochondrial membrane at 2 µM. Besides, both complexes increased apoptosis on three cancer cell lines at low micromolar concentrations (0.5-2.5 µM). Moreover, 1 and 2 inhibited NF-κB pathway both in HT-29-NF-kB-hrGFP monolayer (0.5 to 1 µM) and spheroids HT-29 GFP (5 to 10 µM). This inhibitory effect leads to an inactivation of the MMP-9 expression on HT-29 cell line. Altogether, these results showed that 1 exhibits antiproliferative activity on human colorectal cancer cells in the monolayer and the 3D model.

Synergy of DNA intercalation and catalytic activity of a copper complex towards improved polymerase inhibition and cancer cell cytotoxicity.

Improving the binding of metal complexes to DNA to boost cancer cell cytotoxicity requires fine tuning of their structural and chemical properties. Copper has been used as a metal center in compounds containing intercalating ligands due to its ability to catalytically generate reactive oxygen species (ROS), such as hydroxyl radicals (OH˙). We envision the synergy of DNA binding and ROS generation in proximity to target DNA as a powerful chemotherapy treatment. Here, we explore the use of [Cu(2CP-Bz-SMe)]2+ (2CP-Bz-SMe = 1,3-bis(1,10-phenanthrolin-2-yloxy)-N-(4-(methylthio)benzylidene)propan-2-amine) for this purpose by characterizing its cytotoxicity, DNA binding, and ability to affect DNA replication through the polymerase chain reaction - PCR and nuclease assays. We determined the binding (Kb) and Stern-Volmer constants (KSV) for complex-DNA association of 5.8 ± 0.14 × 104 and 1.64 (±0.08), respectively, through absorption titration and competitive fluorescence experiments. These values were superior to those of other Cu-complex intercalators. We hypothesize that the distorted trigonal bipyramidal geometry of [Cu(2CP-Bz-SMe)]2+ allows the phenanthroline fragments to be better accommodated into the DNA double helix. Moreover, the aromaticity of these fragments increases the local hydrophobicity thus increasing the affinity for the hydrophobic domains of DNA. Nuclease assays in the presence of common reducing agents ascorbic acid, nicotinamide adenine dinucleotide, and glutathione showed the effective degradation of DNA due to the in situ generation of OH˙. The [Cu(2CP-Bz-SMe)]2+ complex showed cytotoxicity against the following human cancer cells lines A549, MCF-7, MDA-MB-231 and MG-63 with half maximal inhibitory concentration (IC50) values of 4.62 ± 0.48, 5.20 ± 0.76, 5.70 ± 0.42 and 2.88 ± 0.66 µM, respectively. These low values of IC50, which are promising if compared to that of cisplatin, are ascribed to the synergistic effect of ROS generation with the intercalation ability into the DNA minor grooves and blocking DNA replication. This study introduces new principles for synergizing the chemical and structural properties of intercalation compounds for improved drug-DNA interactions targeting cancer.

Structure and excited-state dynamics of dimeric copper(i) photosensitizers investigated by time-resolved X-ray and optical transient absorption spectroscopy.

Time-resolved X-ray (tr-XAS) and optical transient absorption (OTA) spectroscopy in the picosecond time scale coupled with Density Functional theory (DFT) and X-ray absorption near-edge structure (XANES) calculations are applied to study three homoleptic Cu(i) dimeric chromophores with ethyl and longer propyl spacers, denoted as [Cu2(mphenet)2]Cl2 (C1), [Cu2(mphenet)2](ClO4)2 (C2) and [Cu2(mphenpr)2](ClO4)2 (C3) (where mphenet = 1,2-bis(9-methyl-1,10-phenanthrolin-2-yl)ethane and mphenpr = 1,3-bis(9-methyl-1,10-phenanthrolin-2-yl)propane). Tr-XAS analysis after light illumination at ∼ 100 ps illustrate the formation of a flattened triplet excited state in all 3 complexes. Optical transient absorption (OTA) analysis for C1 monitored in water and C2 and C3 measured in acetonitrile reveals distinct excited-state lifetimes of 169 ps, 670 ps and 1600 ps respectively. These differences are associated to changes in the solvent (comparing C1 and C2) and the flexibility of the ligand to adapt after Cu flattening upon excitation (C2 and C3). Our results are important for the improved structural dynamics of these types of Cu-based dimeric compounds, and can guide the integration of these chromophores into more complex solar energy conversion schemes.

Structural and Photochemical Properties of Zn(II) Phenanthroline-Derived Complexes: From Mononuclear to Bimetallic and Circular-Trimetallic Helicates.

In the design of self-assembled compounds, small variations in the linkers connecting the coordinating moieties can produce large differences in the obtained structures. Here, we report three novel zinc(II) complexes with phenanthroline-derived ligands as building blocks (L1-L3): A mononuclear complex, a bimetallic helicate, and a trimetallic circular helicate. The even-number spacer in L2 promotes the formation of a bimetallic helicate stabilized by π-π interactions of adjacent phenanthrolines. The addition of an extra methylene in L3 increases the distance between where the phenanthrolines can stack, and CH-π noncovalent interactions give stability to the circular helicate. When irradiated at 308 nm in acetonitrile, long-lived excited states are formed with all three complexes, which are able to participate in oxidation of 2-propanol and in reduction of methylviologen, MV2+. While the overall behavior of the three complexes is similar, the bimetallic helicate is able to form a ground-state adduct with MV2+, while the trimer reaches the excited state to form an exciplex with MV2+.