The monofunctional Pt(II) drug phenanthriplatin is a leading preclinical anticancer drug, whose main characteristic is the presence of the extended aromatic system of the phenanthridine ligand, which allows intercalation. Intercalation, in turn, induces DNA unwinding and facilitates DNA binding. Aiming at verifying to what extent the peculiar cytotoxic activity of phenanthriplatin depends on the specific size of the aromatic system, two phenanthriplatin derivatives have been designed increasing the number of the rings in the N-heterocyclic ligand, and their reactivity has been computationally investigated. Both quantum mechanical DFT computations and molecular dynamics (MD) simulations have been employed to investigate some of the aspects that are considered important for the activity of Pt(II) monofunctional complexes. In particular, the substitution of the chlorido ligand with water, subsequent interaction of the aquated complexes with guanine as a model, eventual deactivation by the model N-acetyl methionine as well as intercalation into, binding to and distortion of DNA have been examined. The outcomes of such analysis have been compared with the analogous ones for the phenanthriplatin complex in order to highlight how the addition of one more ring to the phenanthridine ligand and, eventually, its identity influence the reactivity and, consequently, the cytotoxic profile of the complexes.
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