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

Abstract

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 [Ni4(L1)6]8+ [L1 = 4,4′‐bis(2‐pyridylimine)biphenyl] formulation. The nickel centers have N6 coordination environments with distorted octahedral geometries, and the average Ni–Ni bond length is 12.89 Å. It is exciting that cages 1 and 2 showed effective stabilization of antiparallel G‐quadruplex DNA (ΔTm = 39.09–40.90 °C). Subsequent G‐quadruplex binding studies with analogous cages (3–6) 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 [Fe4(L1)6]8+ (3) and [Fe4(L2)6]8+ (4, L2 = 4,4′‐bis{[1‐(pyridin‐2‐yl)ethylidene]amine}biphenyl) exhibited weaker stabilization effects on G‐quadruplex DNA (ΔTm = 18.33–24.80 °C), and the anionic tetrahedral cages [Fe4(L3)6]4– [5, L3 = 4,4′‐bis(2‐pyridylimine)biphenyl‐2,2′‐disulfonate] and [Ni4(L3)6]4– (6) were inefficient for stabilizing G4 DNA (ΔTm < 1 °C). The remarkable stabilization of G‐quadruplex DNA induced by rigid cages 1 and 2 represent a significant improvement over previously reported flexible Ni4 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.