Design and Synthesis of Novel G4 Ligands through Functionalization of Heterocyclic Scaffolds

G-quadruplexes (G4s) have received considerable attention in recent years, due to evidence of their occurrence in living cells.1 Formed by stacks of guanine quartets, G4s belong to the wide class of non-canonical nucleic acid structures. Putative G4 forming sequences are distributed in genomic regions relevant for a number of pathologies, spanning from cancer to viral infections, where they can act as regulators of genetic information transfer.2 In this context, G4-targeting is regarded as a novel potential therapeutic approach for the treatment of associated diseases.3 Taking inspiration from the recent literature on G4 ligands4 and relying on the scaffold hopping strategy,5 we selected three different heterocyclic frameworks, potentially able to bind G4s by stacking the external G-tetrads. We functionalized these scaffolds with proper polar or positively charged flexible groups for binding to G4 loops/grooves. To investigate the G4 binding properties of the new molecules, biophysical studies were performed employing both telomeric and oncogene promoter G4-forming sequences. Interestingly, the investigated compounds showed potent G4-stabilizing properties and a certain preference for G4 over duplex DNA. Under preliminary in vitro studies, some ligands proved to inhibit cancer cells proliferation, not affecting healthy cells used as control