Hydroxylamido-amino acid complexes of oxovanadium(V). Toxicological study in cell culture and in a zebrafish model.

Oxovanadium(V) complexes [VO(NH(2)O)(2)(val)] and [VO(NH(2)O)(2)(met)] caused inhibition of cell proliferation in two osteoblast cell lines, MC3T3-E1 and UMR106, as well as the viability of zebrafish eggs. In MC3T3-E1, both compounds inhibited cell proliferation (up to ca. 40% at 25 µM [VO(NH(2)O)(2)(val)] and 25% at 25 µM [VO(NH(2)O)(2)(met)]). This effect occurs in a dose response manner from 2.5 µM (p < 0.01) with a more deleterious action of [VO(NH(2)O)(2)(met)]. In UMR106 tumoral cells, [VO(NH(2)O)(2)(val)] inhibited cell proliferation up to 75% from 25 µM while [VO(NH(2)O)(2)(met)] behaved as an inhibitory agent in the whole range of concentrations (p < 0.01). Similar toxic effects were obtained from morphological studies in cell cultures. Moreover, the IC(50) values for both complexes in culture studies correlated with the IC(50) values obtained with an in vivo model of toxicity (FET test). Besides, the cytotoxicity evaluation in cell culture showed a decrease in mitochondrial activity which was stronger for [VO(NH(2)O)(2)(met)] than for [VO(NH(2)O)(2)(val)] (44% vs. 58% at 25 µM) in both cell lines (p < 0.001). Genotoxicity assessed by micronuclei induction also showed a stronger effect of [VO(NH(2)O)(2)(met)] in both cell lines. Besides, [VO(NH(2)O)(2)(val)] caused DNA damage determined by comet formation in MC3T3-E1 cells in the range of 2.5-25 µM, while this effect could not be observed in the osteosarcoma cells. On the other hand, [VO(NH(2)O)(2)(val)] enhanced ROS levels over basal up to 225% and 170% at 100 µM in MC3T3-E1 and UMR106 cells, respectively (p < 0.01). For [VO(NH(2)O)(2)(met)] a similar situation was observed, suggesting an important role for oxidative stress in the toxicity mechanism of action. Although both complexes showed interesting results that would deserve further drug development [VO(NH(2)O)(2)(val)] was more stable than [VO(NH(2)O)(2)(met)] in the solid state. Therefore, we consider that [VO(NH(2)O)(2)(val)] is a good candidate to be tested in in vivo models as a potential antitumoral agent.

Spectroscopic behavior and biological activity of K2[VO(O2)NTA].2H2O.

The dihydrated potassium salt of the complex anion [VO(O(2))NTA](2-) (NTA = nitrilotriacetate anion, [N(CH(2)-COO)(3)](3-)) was thoroughly characterized by electronic and vibrational (infrared and Raman) spectroscopies. The bioactivity of the complex on the cell proliferation was tested on three cell lines in culture (UMR106 rat osteosarcoma-derived cells, Caco-2 derived from a human colon adenocarcinoma, and RAW 264.7, a macrophage murine cell line).

Biological effects of a complex of vanadium(V) with salicylaldehyde semicarbazone in osteoblasts in culture: mechanism of action.

Vanadium compounds display important pharmacological actions in vivo and in vitro systems. Semicarbazones are versatile ligands with therapeutic effects. Herein, we report the effects of V(V)O(2)(salicylaldehydesemicarbazone) (V(V)-Salsem) on two osteoblast cell lines in culture (MC3T3-E1 and UMR106). V(V)-Salsem inhibited cell proliferation in a dose response manner. At 100muM, the complex caused an inhibition of ca. 48% and 38% for the normal and the tumoral osteoblasts, respectively (p<0.001). This inhibition could be partially reversed to 35% and 28% by NAC (N-acetylcysteine) and a mixture of vitamins E and C. Changes in cell proliferation correlated with morphological alterations and the disruption of actin cytoskeleton fibers. The complex also enhanced the level of ROS (reactive oxygen species) up to ca. 100% over basal in both cell lines. Activation of ERK signalling cascade was also observed. These events led to apoptosis (up to 44% in MC3T3-E1 and 33% in UMR106 cells). Scavengers of ROS and inhibitors of ERK cascade allowed to elucidate the mechanisms involved in the cytotoxicity. In conclusion, V(V)-Salsem displayed cytotoxic effects on osteoblasts in culture through the production of free radicals and the activation of ERK cascade. These mechanisms triggered the apoptotic events that conveyed to cell death.

Design of vanadium mixed-ligand complexes as potential anti-protozoa agents.

In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) four novel mixed-ligand vanadyl complexes, [V(IV)O(L(2)-2H)(L(1))], including a bidentate polypyridyl DNA intercalator (L(1)) and a tridentate salycylaldehyde semicarbazone derivative (L(2)) as ligands were synthesized, characterized by a combination of techniques, and in vitro evaluated. EPR suggest a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and the polypyridyl ligand coordinated in an equatorial/axial mode. Both complexes including dipyrido[3,2-a: 2',3'-c]phenazine (dppz) as polypyridyl coligand showed IC(50) values in the muM range against Dm28c strain (epimastigotes) of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal reference drug Nifurtimox. To get an insight into the trypanocidal mechanism of action of these compounds, DNA was evaluated as a potential parasite target and EPR, and (51)V NMR experiments were also carried out upon aging aerated solutions of the complexes. Data obtained by electrophoretic analysis suggest that the mechanism of action of these complexes could include DNA interactions.

Improving anti-trypanosomal activity of 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives by complexation with vanadium.

New vanadium complexes of the type [V(IV)O(L)(2)], where L are 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, were prepared as an effort to obtain new anti-trypanosomal agents improving the bioactivity of the free ligands. Complexation to vanadium of the quinoxaline ligands leads to excellent antiprotozoal activity, similar to that of the reference drugs nifurtimox and benznidazole and in all cases higher than that of the corresponding free ligands. In addition, it is for the first time that the V((IV))O-quinoxaline complexes are reported as a family of anti-Trypanosoma cruzi agents. Finally, the anti-trypanosomal activity of these vanadium complexes could be explained on the basis of their lipophilicity and the electronic characteristics of the quinoxaline substituents.