Five new anionic aqueous dioxidovanadium­(V) complexes, [{VO2L1,2}­A­(H2O) n ]α (1–5), with the aroylhydrazone ligands pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)­hydrazide (H2L1) and furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)­hydrazide (H2L2) incorporating different alkali metals (A = Na+, K+, Cs+) as countercation were synthesized and characterized by various physicochemical techniques. The solution-phase stabilities of 1–5 were determined by time-dependent NMR and UV–vis, and also the octanol/water partition coefficients were obtained by spectroscopic techniques. X-ray crystallography of 2–4 confirmed the presence of vanadium­(V) centers coordinated by two cis-oxido-O atoms and the O, N, and O atoms of a dianionic tridentate ligand. To evaluate the biological behavior, all complexes were screened for their DNA/protein binding propensity through spectroscopic experiments. Finally, a cytotoxicity study of 1–5 was performed against colon (HT-29), breast (MCF-7), and cervical (HeLa) cancer cell lines and a noncancerous NIH-3T3 cell line. The cytotoxicity was cell-selective, being more active against HT-29 than against other cells. In addition, the role of hydrophobicity in the cytotoxicity was explained in that an optimal hydrophobicity is essential for high cytotoxicity. Moreover, the results of wound-healing assays indicated antimigration in case of HT-29 cells. Remarkably, 1 with an IC50 value of 5.42 ± 0.15 μM showed greater activity in comparison to cisplatin against the HT-29 cell line.

A series of mononuclear non-oxido vanadium(IV) [V(IV)(L(1-4))2] (1-4), oxidoethoxido vanadium(V) [V(V)O(L(1-4))(OEt)] (5-8), and dinuclear μ-oxidodioxidodivanadium(V) [V(V)2O3(L(1))2] (9) complexes with tridentate aroylazine ligands are reported [H2L(1) = 2-furoylazine of 2-hydroxy-1-acetonaphthone, H2L(2) = 2-thiophenoylazine of 2-hydroxy-1-acetonaphthone, H2L(3) = 1-naphthoylazine of 2-hydroxy-1-acetonaphthone, H2L(4) = 3-hydroxy-2-naphthoylazine of 2-hydroxy-1-acetonaphthone]. The complexes are characterized by elemental analysis, by various spectroscopic techniques, and by single-crystal X-ray diffraction (for 2, 3, 5, 6, 8, and 9). The non-oxido V(IV) complexes (1-4) are quite stable in open air as well as in solution, and DFT calculations allow predicting EPR and UV-vis spectra and the electronic structure. The solution behavior of the [V(V)O(L(1-4))(OEt)] compounds (5-8) is studied confirming the formation of at least two different types of V(V) species in solution, monomeric corresponding to 5-8, and μ-oxidodioxidodivanadium [V(V)2O3(L(1-4))2] compounds. The μ-oxidodioxidodivanadium compound [V(V)2O3(L(1))2] (9), generated from the corresponding mononuclear complex [V(V)O(L(1))(OEt)] (5), is characterized in solution and in the solid state. The single-crystal X-ray diffraction analyses of the non-oxido vanadium(IV) compounds (2 and 3) show a N2O4 binding set and a trigonal prismatic geometry, and those of the V(V)O complexes 5, 6, and 8 and the μ-oxidodioxidodivanadium(V) (9) reveal that the metal center is in a distorted square pyramidal geometry with O4N binding sets. For the μ-oxidodioxidodivanadium species in equilibrium with 5-8 in CH2Cl2, no mixed-valence complexes are detected by chronocoulometric and EPR studies. However, upon progressive transfer of two electrons, two distinct monomeric V(IV)O species are detected and characterized by EPR spectroscopy and DFT calculations.

The synthesis and characterization of one oxidoethoxidovanadium­(V) [VVO­(L1)­(OEt)] (1) and two nonoxidovanadium­(IV) complexes, [VIV(L2–3)2] (2 and 3), with aroylhydrazone ligands incorporating naphthalene moieties, are reported. The synthesized oxido and nonoxido vanadium complexes are characterized by various physicochemical techniques, and their molecular structures are solved by single crystal X-ray diffraction (SC-XRD). This revealed that in 1 the geometry around the vanadium atom corresponds to a distorted square pyramid, with a O4N coordination sphere, whereas that of the two nonoxido VIV complexes 2 and 3 corresponds to a distorted trigonal prismatic arrangement with a O4N2 coordination sphere around each “bare” vanadium center. In aqueous solution, the VVO moiety of 1 undergoes a change to VVO2 species, yielding [VVO2(L1)]− (1′), while the nonoxido VIV-compounds 2 and 3 are partly converted into their corresponding VIVO complexes, [VIVO­(L2–3)­(H2O)] (2′ and 3′). Interaction of these VVO2, VIVO, and VIV systems with two model proteins, ubiquitin (Ub) and lysozyme (Lyz), is investigated through docking approaches, which suggest the potential binding sites: the interaction is covalent for species 2′ and 3′, with the binding to Glu16, Glu18, and Asp21 for Ub, and His15 for Lyz, and it is noncovalent for species 1′, 2, and 3, with the surface residues of the proteins. The ligand precursors and complexes are also evaluated for their in vitro antiproliferative activity against ovarian (A2780) and prostate (PC3) human cancer cells and in normal fibroblasts (V79) to check the selectivity of the compounds for cancer cells.

The synthesis, structure and characterization of mixed ligand oxidovanadium(iv) complexes [V^IVOL^1–2(L^N–N)] (1–3) are reported. With a view to evaluating their biological activity, their DNA/HSA interaction and cytotoxicity activity have been explored.

The transport and cytotoxicity of molybdenum-based drugs have been explained with the concept of chemical transformation, a very important idea in inorganic medicinal chemistry that is often overlooked in the interpretation of the biological activity of metal-containing systems. Two monomeric, [MoO2(L1)­(MeOH)] (1) and [MoO2(L2)­(EtOH)] (2), and two mixed-ligand dimeric MoVIO2 species, [{MoO2(L1–2)}2(μ-4,4′-bipy)] (3–4), were synthesized and characterized. The structures of the solid complexes were solved through SC-XRD, while their transformation in water was clarified by UV–vis, ESI-MS, and DFT. In aqueous solution, 1–4 lead to the penta-coordinated [MoO2(L1–2)] active species after the release of the solvent molecule (1 and 2) or removal of the 4,4′-bipy bridge (3 and 4). [MoO2(L1–2)] are stable in solution and react with neither serum bioligand nor cellular reductants. The binding affinity of 1–4 toward HSA and DNA were evaluated through analytical and computational methods and in both cases a non-covalent interaction is expected. Furthermore, the in vitro cytotoxicity of the complexes was also determined and flow cytometry analysis showed the apoptotic death of the cancer cells. Interestingly, μ-4,4′-bipy bridged complexes 3 and 4 were found to be more active than monomeric 1 and 2, due to the mixture of species generated, that is [MoO2(L1–2)] and the cytotoxic 4,4′-bipy released after their dissociation. Since in the cytosol neither the reduction of MoVI to MoV/IV takes place nor the production of reactive oxygen species (ROS) through Fenton-like reactions of 1–4 with H2O2 occurs, the mechanism of cytotoxicity should be attributable to the direct interaction with DNA that happens with a minor-groove binding which results in cell death through an apoptotic mechanism.