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, [MoO(L)(MeOH)] () and [MoO(L)(EtOH)] (), and two mixed-ligand dimeric MoO species, [{MoO(L)}(μ-4,4'-bipy)] (-), 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, - lead to the penta-coordinated [MoO(L)] active species after the release of the solvent molecule ( and ) or removal of the 4,4'-bipy bridge ( and ). [MoO(L)] are stable in solution and react with neither serum bioligand nor cellular reductants. The binding affinity of - toward HSA and DNA were evaluated through analytical and computational methods and in both cases a non-covalent interaction is expected. Furthermore, the 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 and were found to be more active than monomeric and , due to the mixture of species generated, that is [MoO(L)] and the cytotoxic 4,4'-bipy released after their dissociation. Since in the cytosol neither the reduction of Mo to Mo takes place nor the production of reactive oxygen species (ROS) through Fenton-like reactions of - with HO 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.