Mirror‐Image Dependence: Targeting Enantiomeric G‐Quadruplex DNA Using Triplex Metallohelices

Natural d ‐DNA and l ‐DNA are mirror‐image counterparts. However, because of the inherent flexibility and conformation diversity of DNA, it is still not clear how enantiomeric compounds recognize d ‐DNA and l ‐DNA. Herein, taking G‐quadruplex (G4) DNA as an example that has diverse conformations and distinct biofunctions, the binding of ten pairs of iron triplex metallohelices to d ‐ and l ‐G4 DNA were evaluated. The Δ‐enantiomer binds to d ‐DNA and the Λ‐enantiomer binds to l ‐DNA, exhibiting almost the same stabilization effect and binding affinity. The binding affinity of the Δ‐metallohelix with d ‐G4 is nearly 70‐fold higher than that of Λ‐metallohelix binding d ‐G4. Δ‐Metallohelix binding to d ‐G4 follows a two‐step binding process driven by a favorable enthalpy contribution to compensate for the associated unfavorable entropy.