Speciation and biorelevant reactions of the potential anti-tumor agent vanadocene dichloride

Vanadium compounds exhibit a wide variety of pharmacological properties, like antidiabetic and anti-tumor. Among the vanadium compounds with anti-tumor activity, vanadocene dichloride ([Cp2VCl2] or VDC) has been proposed since 1983 in the treatment of Ehrlich ascites tumor. Despite all VDC derivatives studied subsequently showed high activity in human cancer cells, their mechanism of action is not fully known. In particular, biotransformation in the plasma and in the cellular environment remains elusive and, therefore, it needs to be explored if and how VDC or its derivatives could bind to the bioligands of serum and cytosol after oral administration. In fact the assumption that V compounds reach the target cells in the same form as they are administrated is an oversimplification. Indeed, in the blood several displacement, exchange and complexation reactions are possible and the generated fragments can interact with low molecular mass bioligands and proteins; moreover, the V species can distribute between plasma and erythrocytes. In this work, the interaction of VDC with several components of the blood serum (oxalate, lactate, phosphate, citrate and amino acids among those with low molecular mass and transferrin and albumin among the proteins) and its uptake by red blood cells were studied through the combined application of spectroscopic (EPR, ESI-MS and electronic absorption spectroscopy) and computational (DFT) methods. Moreover, the interaction of VDC with some relevant cellular bioligands, such as proteins (hemoglobin), amino acids (glycine and histidine), NADH derivatives (NADH, NADPH, NAD+ and NAPD+), reductants (GSH and ascorbic acid), phosphates (HPO42-, P2O74-, cAMP, AMP, ADP and ATP) and DNA, the DNA cleavage activity and the capability to generate OH radicals were studied. This transformation in the cellular environment could be related to the mechanism of action of VDC.