ESI-MS Study of the Interaction of Potential Oxidovanadium(IV) Drugs and Amavadin with Model Proteins

In this study, the binding to lysozyme (Lyz) of four important V^IV compounds with antidiabetic and/or anticancer activity, [V^IVO­(pic)₂(H₂O)], [V^IVO­(ma)₂], [V^IVO­(dhp)₂], and [V^IVO­(acac)₂], where pic^–, ma^–, dhp^–, and acac^– are picolinate, maltolate, 1,2-dimethyl-3-hydroxy-4­(1H)-pyridinonate, and acetylacetonate anions, and of the vanadium-containing natural product amavadin ([V^IV(hidpa)₂]^2–, with hidpa^3– N-hydroxyimino-2,2′-diisopropionate) was investigated by ElectroSpray Ionization-Mass Spectrometry (ESI-MS). Moreover, the interaction of [V^IVO­(pic)₂(H₂O)], chosen as a representative V^IVO²⁺ complex, was examined with two additional proteins, myoglobin (Mb) and ubiquitin (Ub), to compare the data. The examined vanadium concentration was in the range 15–150 μM, i.e., very close to that found under physiological conditions. With pic^–, dhp^–, and hidpa^3–, the formation of adducts n[V^IVOL₂]–Lyz or n[V^IVL₂]–Lyz is favored, while with ma^– and acac^– the species n[V^IVOL]–Lyz are detected, with n dependent on the experimental V^IV/protein ratio. The behavior of the systems with [V^IVO­(pic)₂(H₂O)] and Mb or Ub is very similar to that of Lyz. The results suggested that under physiological conditions, the moiety cis-V^IVOL₂ (L = pic^–, dhp^–) is bound by only one accessible side-chain protein residue that can be Asp, Glu, or His, while V^IVOL⁺ (L = ma^–, acac^–) can interact with the two equatorial and axial sites. If the V^IV complex is thermodynamically stable and does not have available coordination positions, such as amavadin, the protein cannot interact with it through the formation of coordination bonds and, in such cases, noncovalent interactions are predicted. The formation of the adducts is dependent on the thermodynamic stability and geometry in aqueous solution of the V^IVO²⁺ complex and affects the transport, uptake, and mechanism of action of potential V drugs.