Mo(VI) Potential Metallodrugs: Explaining the Transport and Cytotoxicity by Chemical Transformations
Monalisa Mohanty, Gurunath Sahu, Atanu Banerjee, Sudhir Lima, Sushree Aradhana Patra, Aurélien Crochet, Giuseppe Sciortino, Daniele Sanna, Valeria Ugone, Eugenio Garribba, Rupam Dinda
Abstract
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 MoVIO2 species, [{MoO2(L1–2)}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(L1–2)] active species after the release of the solvent molecule (1 and 2) or removal of the 4,4′-bipy bridge (3 and 4). [MoO2(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 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(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 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.