Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex

Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal‐containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B‐DNA. G‐quadruplex nucleic acid, obtained by self‐assembly of guanine‐rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G‐quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner‐ and outer‐sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G‐quadruplex DNA prevalently, either establishing π‐stacking nteractions with the terminal G‐tetrad or through electrostatic interactions along with H‐bonds formation.