Threading Bis-Intercalation of a Macrocyclic Bisacridine at Abasic Sites in DNA: Nuclear Magnetic Resonance and Molecular Modeling Study

Abstract

The macrocyclic bisacridine (CBA) has been reported previously to specifically recognize single-stranded nucleic acid structures, especially DNA hairpins. The binding of the drug with an abasic site-containing oligonucleotide, was investigated by ¹H NMR and molecular modeling. We have used a DNA undecamer, the d(C₁G₂C₃A₄C₅X₆C₇A₈C₉G₁₀C₁₁)·d(G₁₂C₁₃G₁₄T₁₅G₁₆T₁₇G₁₈T₁₉G₂₀C₂₁G₂₂) duplex in which the X residue is a stable analogue of the abasic site [3-hydroxy-2-(hydroxymethyl) tetrahydrofuran]. Analysis of the NMR data reveals that the bisacridine molecule forms two different intercalation complexes in a 80/20 (± 10) ratio. For the major complex, a molecular modeling study was performed guided by nineteen intermolecular drug−DNA restraints, determined from NOESY spectra. In this model, the ligand interacts in the threading binding mode with an acridine ring intercalated between the C₇−A₈ and T₁₅−G₁₆ base pairs, while the other acridine ring resides in the abasic pocket. The two linker chains are positioned in the minor and in the major groove, respectively. A comparable study was performed to evaluate the interaction of CBA with the parent unmodified duplex in which X₆ was replaced by an adenine residue. No complex formation was observed when operating in identical conditions. This shows the selective binding of CBA to the abasic site and its potential interest to target the abasic site lesion.