Biospeciation of Potential Vanadium Drugs of Acetylacetonate in the Presence of Proteins

Giuseppe Sciortino; Valeria Ugone; Daniele Sanna; Giuseppe Lubinu; Simone Ruggiu; Jean-Didier Maréchal; Eugenio Garribba

doi:10.3389/fchem.2020.00345

Biospeciation of Potential Vanadium Drugs of Acetylacetonate in the Presence of Proteins

Front Chem. 2020 May 7:8:345. doi: 10.3389/fchem.2020.00345. eCollection 2020.

Authors

Giuseppe Sciortino^{1

2}, Valeria Ugone¹, Daniele Sanna³, Giuseppe Lubinu¹, Simone Ruggiu¹, Jean-Didier Maréchal², Eugenio Garribba¹

Affiliations

¹ Dipartimento di Chimica e Farmacia, Università di Sassari, Sassari, Italy.
² Departament de Química, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Barcelona, Spain.
³ Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Sassari, Italy.

Abstract

Among vanadium compounds with potential medicinal applications, [V^IVO(acac)₂] is one of the most promising for its antidiabetic and anticancer activity. In the organism, however, interconversion of the oxidation state to +III and +V and binding to proteins are possible. In this report, the transformation of V^III(acac)₃, V^IVO(acac)₂, and V^VO₂(acac) $_{2}^{-}$ after the interaction with two model proteins, lysozyme (Lyz) and ubiquitin (Ub), was studied with ESI-MS (ElectroSpray Ionization-Mass Spectroscopy), EPR (Electron Paramagnetic Resonance), and computational (docking) techniques. It was shown that, in the metal concentration range close to that found in the organism (15-250 μM), V^III(acac)₃ is oxidized to V^IVO(acac)⁺ and V^IVO(acac)₂, which-in their turn-interact with proteins to give n[V^IVO(acac)]-Protein and n[V^IVO(acac)₂]-Protein adducts. Similarly, the complex in the +IV oxidation state, V^IVO(acac)₂, dissociates to the mono-chelated species V^IVO(acac)⁺ which binds to Lyz and Ub. Finally, V^VO₂(acac) $_{2}^{-}$ undergoes complete dissociation to give the 'bare' V^VO $_{2}^{+}$ ion that forms adducts n[V^VO₂]-Protein with n = 1-3. Docking calculations allowed the prediction of the residues involved in the metal binding. The results suggest that only the V^IVO complex of acetylacetonate survives in the presence of proteins and that its adducts could be the species responsible of the observed pharmacological activity, suggesting that in these systems V^IVO²⁺ ion should be used in the design of potential vanadium drugs. If V^III or V^VO₂ potential active complexes had to be designed, the features of the organic ligand must be adequately modulated to obtain species with high redox and thermodynamic stability to prevent oxidation and dissociation.

Keywords: anticancer action; antidiabetic action; drug design; metal drugs; proteins; transport in the organism; vanadium.