Enhanced Stabilization of G‐Quadruplex DNA by [Ni4L6]8+ Cages with Large Rigid Aromatic Ligands

Two tetrahedral nickel(II) cages, [Ni4L6](8+) (1 and 2), with large rigid aromatic ligands were synthesized, and their G-quadruplex DNA binding abilities were investigated. The crystal structure of cage 1 confirmed its tetrahedral [Ni-4(L1)(6)](8+) [L1 = 4,4'-bis(2-pyridylimine) biphenyl] formulation. The nickel centers have N-6 coordination environments with distorted octahedral geometries, and the average Ni-Ni bond length is 12.89 angstrom. It is exciting that cages 1 and 2 showed effective stabilization of antiparallel G-quadruplex DNA (Delta T-m = 39.09-40.90 degrees C). Subsequent G-quadruplex binding studies with analogous cages (36) were performed to explore the impact of the central metal ion and the overall charge on the interaction with G-quadruplex DNA. The corresponding iron(II) cages [Fe-4(L1)(6)](8+) (3) and Fe-4(L2)(6)](8+) (4, L2 = 4,4'-bis{[1-(pyridin-2-yl)ethylidene]amine}-biphenyl) exhibited weaker stabilization effects on G-quadruplex DNA (Delta T-m = 18.33-24.80 degrees C), and the anionic tetrahedral cages [Fe-4(L3)(6)](4-)[5, L3 = 4,4'-bis(2-pyridylimine) biphenyl-2,2'disulfonate] and [Ni-4(L3)(6)](4-)(6) were inefficient for stabilizing G4 DNA (Delta T-m < 1 degrees C). The remarkable stabilization of G-quadruplex DNA induced by rigid cages 1 and 2 represent a significant improvement over previously reported flexible Ni-4 cages. These results indicate that central metal ion, overall charge, and structural rigidity of the tetrahedral cage play critical roles in G-quadruplex stabilization and provide new insight into the interactions between tetrahedral cages and G-quadruplex DNA.