Mixed-Ligand Complex Formation in the Systems Containing the Potential Drug [VIVO(acac)2] with Blood and Cellular Bioligands. Implications on the Active Species Formed in the Organism

Bis(acetylacetonato)oxidovanadium(IV), [VIVO(acac)2], is one of the most widely studied VIV complexes with remarkable biological activities. However, the interaction of [VIVO(acac)2] with the serum and cytosol relevant bioligands (bLs) has not been systematically investigated. Here, we present an integrated study of the ternary systems VIVO2+/acac/bL (where bL is lactate, citrate, oxalate, histidine, cysteine, aspartate, pyrophosphate, ATP, and reduced glutathione) by pH-potentiometry, electrospray ionization-mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR), UV-vis, and circular dichroism (CD). Stability constants were determined for VIVO-acac and VIVO-acac-bL complexes, showing that significant amounts of mixed-ligand species form in most of the ternary systems, whose distribution is strongly pH- and bL-dependent. EPR measurements allowed obtaining insights into the binding modes of bLs. Mass, UV-vis, and CD spectra confirmed the existence of the proposed ternary species in solution. The thermodynamic data were used to model the speciation of [VIVO(acac)2] in the blood serum, in erythrocytes, and cancer cell cytosol, showing that when V concentration is larger than 10-20 μM, [VIVO(acac)(citrato)]2-, [VIVO(acac)(P2O7)]3-, and, secondarily, [VIVO(acac)(histidinato)] and [VIVO(acac)(aspartato)]- become relevant species. The findings, besides clarifying the solution chemistry of [VIVO(acac)2] in biologically relevant environments, also highlight the likely role of mixed-ligand VIVO(acac)(bL) complexes in its transport, accumulation, and pharmacological activity.