Modular Symmetric Ligands for Selective Recognition of Cancer-Relevant G-Quadruplexes

New G-quadruplex-interactive and selective ligands are strongly required to evolve innovative, effective and minimally toxic anticancer agents. With this purpose, we have here synthesised and evaluated a mini-library of organic molecules featured by aromatic cores of different rigidity (naphthalene or bioxazole), decorated with pendant groups including positively charged moieties and/or H-bond donors/acceptors. By exploiting different biophysical techniques, we proved the ability of the bioxazole-based derivatives to strongly and selectively interact with telomeric and oncogenic G-quadruplexes, while the compound featured by a naphthalene core did not emerge as a good G-quadruplex ligand. Molecular docking studies demonstrated the ability of the bioxazole-based ligands to preferentially target the outer G-tetrads of both telomeric and oncogenic G-quadruplexes, by positioning their cores on the G-tetrads in a symmetrical or asymmetrical way respectively, with the pendant groups pointing towards or away from the grooves. All bioxazole-based ligands showed anticancer activity in the low micromolar range. Particularly, the bioxazole derivative bearing piperazine groups was the most active compound of the investigated series, whereas the derivatives bearing morpholine groups were the most selective ones on cancer cells, in full agreement with their ability to act as the strongest and most selective G-quadruplex ligands, respectively.