Speciation of the Potential Antitumor Agent Vanadocene Dichloride in the Blood Plasma and Model Systems

Abstract

The speciation of the potential antitumor agent vanadocene dichloride ([Cp2VCl2], abbreviated with VDC) in the blood plasma was studied by instrumental (EPR, ESI-MS, MS-MS, and electronic absorption spectroscopy) and computational (DFT) methods. The behavior of VDC at pH 7.4 in aqueous solution, the interaction with the most important bioligands of the plasma (oxalate, carbonate, phosphate, lactate, citrate, histidine, and glycine among those with low molecular mass and transferrin and albumin between the proteins) was evaluated. The results suggest that [Cp2VCl2] transforms at physiological pH to [Cp2V(OH)2] and that only oxalate, carbonate, phosphate, and lactate are able to displace the two OH(-) ions to yield [Cp2V(ox)], [Cp2V(CO3)], [Cp2V(lactH(-1))], and [Cp2V(HPO4)]. The formation of the adducts with oxalate, carbonate, lactate, and hydrogen phosphate was confirmed also by ESI-MS and MS-MS spectra. The stability order is [Cp2V(ox)] ≫ [Cp2V(CO3)] > [Cp2V(lactH(-1))] > [Cp2V(HPO4)]. No interaction between VDC and plasma proteins was detected under our experimental conditions. Several model systems containing the bioligands (bL) in the same relative ratio as in the blood samples were also examined. Finally, the speciation of VDC in the plasma was studied. The results obtained show that the model systems behave as the blood plasma and indicate that when V concentration is low (10 μM) VDC is transported in the bloodstream as [Cp2V(ox)]; when V concentration is high (100 μM) oxalate binds only 9.2 μM of [Cp2V](2+), whereas the remaining part distributes between [Cp2V(CO3)] (main species) and [Cp2V(lactH(-1))] (minor species); and when V concentration is in the range 10-100 μM [Cp2V](2+) distributes between [Cp2V(ox)] and [Cp2V(CO3)].

Stabilities and Biological Activities of Vanadium Drugs: What is the Nature of the Active Species?

“…Metallocene dichlorides (Cp 2 M IV Cl 2 , where M=V IV , Mo IV or Ti IV ) were studied as potential anti‐cancer drugs for several decades, but have not translated into the clinic . The likely main reason for unsatisfactory performance in pre‐clinical studies was their rapid hydrolysis in blood serum, leading to poor cellular uptake . Therefore, a new generation of vanadocene complexes features sterically hindered ligands that lead to improved stability in biological media and higher cellular uptake, such as 14 , which surpassed the cytotoxicity of a previously proposed derivative, 15 (vanadocene Y), as shown in Table S1.…”

Vanadium, Ruthenium and Copper Compounds: A New Class of Nonplatinum Metallodrugs with Anticancer Activity

“…1). Besides, in vivo studies revealed that vanadocene compounds exhibit significant antitumor properties with vanadocene dichloride being one of the most promising among metallocenes [33] [34]. Several vanadocene derivatives, especially the methyl-and methoxy-substituted vanadocene dichlorides showed cytotoxic effects against T-lymphocytic leukemia cells with MOLT-4 evidencing more activity than their corresponding titanocene analogs.…”

Non‐Oxido‐Vanadium(IV) Metalloradical Complexes with Bidentate 1,2‐Dithienylethene Ligands: Observation of Reversible Cyclization of the Ligand Scaffold in Solution

“…[12] Vanadocene dichloridea nd derivatives thereof have been investigated with respect to their antitumor activity. [13] Vanadium coordination compounds show ab road range of potential applications in medicinal chemistry including the treatment of endemic tropical and various heart muscle diseases. Ac oncise overview was recently given by Rehder.…”

“…A prominent compound is amavadin, which is a naturally occurring example of a non‐oxido V IV coordination complex, which was initially isolated from the toadstool Amanita muscaria . Vanadocene dichloride and derivatives thereof have been investigated with respect to their antitumor activity . Vanadium coordination compounds show a broad range of potential applications in medicinal chemistry including the treatment of endemic tropical and various heart muscle diseases.…”