Abstract
Targeting and stabilizing nonclassical DNA G-quadruplexes (G4s) with a ligand to inhibit cell proliferation is a very promising approach for cancer treatment. Here, we demonstrate that the combination of a naphthalenediimide (NDI) ligand and a squaraine ligand significantly improves the anticancer activity of either ligand alone. The NDI ligand binds the 5'-terminal of hybrid-type G4s and induces the topological conversion from a metastable hybrid to a stable parallel conformation, which allows the end-stacking of the squaraine ligand on the 3'-terminal of the resultant parallel-type G4 structure. Moreover, the NDI ligand promotes the diffusion of the squaraine ligand into the nucleus, and the synergistic effect of the two ligands improves the stability of G4s in cancer cells, blocks the cell cycle in the sub-G1 phase, and induces the DNA damage response. These findings will be helpful in the development of combinational ligands targeting DNA G4s with enhanced bioactivity toward the inhibition of cancer cell proliferation.