Explaining the Transport and Cytotoxicity Potential of Mo(VI)-based drugs by Chemical Transformations

Abstract

The transport and cytotoxicity of molybdenum-based drugs have been explained with the concept of chemical transformation, an important idea in inorganic medicinal chemistry that is often overlooked in the interpretation of the biological activity. Two monomeric, [MoO2(L1)(MeOH)] (1) and [MoO2(L2)(EtOH)] (2), and two mixed-ligand dimeric MoVIO2 species, [{MoO2(L1−2)}2(μ-4,4′-bipy)] (3−4), were synthesized and characterized.1 The structures of the complexes were solved through SC-XRD, while their transformation in water was clarified by UV−vis, ESI-MS, and DFT. In aqueous solution, 1−4 leads to the pentacoordinated [MoO2(L1−2)] active species after the release of the solvent molecule (1 and 2) or removal of the 4,4′-bipy (3 and 4). [MoO2(L1−2)] are stable in solution and react with neither serum bioligand nor cellular reductants. The binding affinity of 1−4 toward HSA and DNA was evaluated through analytical and computational methods and in both cases, a non-covalent interaction is expected. In vitro cytotoxicity of the complexes was also determined2,3 and flow cytometry analysis showed apoptotic cell death. Interestingly, μ-4,4′-bipy bridged complexes 3 and 4 were found to be more active than monomeric and 2, due to the mixture of species generated, that is [MoO2(L1−2)] and the cytotoxic 4,4′-bipy released after their dissociation. Since in the cytosol neither the reduction of MoVI to MoV/IV takes place nor the production of ROS through Fenton-like reactions of 1−4 with H2O2 occurs, the mechanism of cytotoxicity should be attributable to the direct interaction with DNA that happens with a minor-groove binding which results in cell death through an apoptotic mechanism.