Mo(VI) Potential Metallodrugs: Explaining the Transport and Cytotoxicity by Chemical Transformations

The transport and cytotoxicity of molybdenum-based drugs have been explained with the concept of chemical transformation, a very important idea in inorganic medicinal chemistry that is often overlooked in the interpretation of the biological activity of metal-containing systems. Two monomeric, [MoO₂(L¹)(MeOH)] (1) and [MoO₂(L²)(EtOH)] (2), and two mixed-ligand dimeric Mo^VIO₂ species, [{MoO₂(L^1-2)}₂(μ-4,4'-bipy)] (3-4), were synthesized and characterized. The structures of the solid 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 lead to the penta-coordinated [MoO₂(L^1-2)] active species after the release of the solvent molecule (1 and 2) or removal of the 4,4'-bipy bridge (3 and 4). [MoO₂(L^1-2)] are stable in solution and react with neither serum bioligand nor cellular reductants. The binding affinity of 1-4 toward HSA and DNA were evaluated through analytical and computational methods and in both cases a non-covalent interaction is expected. Furthermore, the in vitro cytotoxicity of the complexes was also determined and flow cytometry analysis showed the apoptotic death of the cancer cells. Interestingly, μ-4,4'-bipy bridged complexes 3 and 4 were found to be more active than monomeric 1 and 2, due to the mixture of species generated, that is [MoO₂(L^1-2)] and the cytotoxic 4,4'-bipy released after their dissociation. Since in the cytosol neither the reduction of Mo^VI to Mo^V/IV takes place nor the production of reactive oxygen species (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.