Naphthalene diimide-naphthalimide dyads promote telomere damage by selectively targeting multimeric G-quadruplexes

G-quadruplex (G4) nucleic acid ligands have attracted significant attention as putative anticancer agents for selectively stabilizing telomeric structures. In our pursuit of targeting the most biologically relevant telomeric structures, we have investigated a new class of naphthalene diimide (NDI)-based ligands designed to bind multimeric G4s. The NDI unit covalently linked with one 1,8-naphthalimide (NI) moiety, results in ligands able to fold into a sandwich-like conformation fitting into the binding pockets of telomeric multimeric G4s, thus optimizing binding complementarity. Varying the NDI decorations, we synthesized a small library of NDI-NI dyads and then examined their capability of stabilizing G4s by biophysical assays. Given the relevance of G4 stabilizing agents in fighting cancer, the most promising NDI-NIs were evaluated for their antitumoral activity on a panel of human cell lines originating from different tumor histotypes. Obtained results evidenced that three of the selected ligands promoted an accumulation of telomere-localized damage leading to a robust impairment of cell viability, regardless of homologous recombination status. These data, then confirmed in advanced 3D models, paved the way for the advancement of NDI-NIs as a new class of clinically relevant antitumoral agents. Finally, computational analyses gained deeper insight into their binding modality.