Luisa D'Anna, Riccardo Rozza, Aurane Froux, Christian Jandl, Simona Rubino, Angelo Spinello, Lorenza La Rosa, Carla Gentile, Alessandra Magistrato, Alessio Terenzi, Riccardo Bonsignore, Giampaolo Barone
Three nickel(II), copper(II), and zinc(II) salnaphen complexes, bearing structurally related charged side chains, were designed to elucidate the role of substituent size and shape in determining their binding strength and affinity for G-quadruplex (G4) DNA structures. Solution DNA-binding studies revealed that aromatic complexes exhibited enhanced G4 stabilization compared to non-aromatic analogues, with copper(II) complexes displaying the strongest affinity and a marked sequence-dependent DNA-binding profile. Molecular dynamics simulations provide a structural rationale for these observations, revealing for the first time that aromatic substituents foster more persistent end-stacking interactions and enhanced stability of the metal complex-G4 system, bridging ligand design, G4 recognition, and biological response. Consistently, the most effective G4 stabilizer also exhibits measurable antiproliferative activity in vitro, associated with pronounced reactive oxygen species (ROS) generation, highlighting how G4 targeting and redox-mediated cytotoxicity-two features only rarely addressed together-can be effectively combined within a single molecular framework.