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 2 (L 1 )(MeOH)] ( 1 ) and [MoO 2 (L 2 )(EtOH)] ( 2 ), and two mixed-ligand dimeric Mo VI O 2 species, [{MoO 2 (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 [MoO 2 (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 ). [MoO 2 (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 [MoO 2 (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 H 2 O 2 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.