Biorelevant reactions of the potential anti-tumor agent vanadocene dichloride

Abstract

The interaction of the potential anti-tumor agent vanadocene dichloride ([Cp₂VCl₂] or VDC) with some relevant bioligands of the cytosol such as proteins (Hb), amino acids (glycine and histidine), NADH derivatives (NADH, NADPH, NAD⁺ and NADP⁺), reductants (GSH and ascorbic acid), phosphates (HPO₄²⁻, P₂O₇⁴⁻, cAMP, AMP, ADP and ATP) and carboxylate derivatives (lactate) and its uptake by red blood cells were studied. The results indicated that [Cp₂VCl₂] transforms at physiological pH into [Cp₂V(OH)₂] and that only HPO₄²⁻, P₂O₇⁴⁻, lactate, ATP and ADP form mixed species with the [Cp₂V]²⁺ moiety replacing the two hydroxide ions. EPR and electronic absorption spectroscopy, agarose gel electrophoresis and spin trapping measurements allow excluding any direct interaction and/or intercalation with DNA and the formation of reactive oxygen species (ROS) in Fenton-like reactions. Uptake experiments by erythrocytes suggested that VDC crosses the membrane and enters inside the cells, whereas ‘bare’ V^IV transforms into V^IVO species with loss of the two cyclopentadienyl rings. This transformation in the cellular environment could be related to the mechanism of action of VDC.