The effect of intercalator structure on binding strength and base-pair specificity in DNA interactions

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysical Chemistry

Background:

• Aromatic compounds with cationic side chains are synthesized using aromatic acid chlorides, amines, and alcohols.
• Understanding the interaction of these novel compounds with DNA is crucial for potential therapeutic applications.

Purpose of the Study:

• To investigate the DNA binding mechanisms of naphthothiophene, phenanthrene, and anthracene derivatives with amide and ester side chains.
• To elucidate the structure-activity relationships governing the interaction between these intercalators and DNA.
• To determine the sequence specificity of DNA binding for these novel compounds.

Main Methods:

• Viscometric titrations were employed to assess DNA structural changes upon compound binding.
• Spectrophotometric binding experiments quantified binding affinities and constants.
• Nuclear Magnetic Resonance (NMR) spectroscopy (1H, 31P, 17O) provided detailed insights into the binding mode and molecular interactions.

Main Results:

• Viscosity and NMR data indicate that all tested compounds intercalate into the DNA structure.
• Significant variations in DNA binding affinity were observed, correlated with the geometry of the aromatic ring systems and the nature/position of side chains.
• Compounds exhibited a stronger binding affinity for poly[d(A-T)2] compared to poly[d(G-C)2], suggesting A-T sequence preference.

Conclusions:

• The intercalation mode of DNA binding is confirmed for these aromatic compounds.
• Molecular geometry and side chain properties significantly influence DNA binding affinity and specificity.
• A model involving solvent-mediated hydrogen bonding explains the observed A-T sequence preference, particularly for ester derivatives.