Hexahelicene DNA-binding: Minor groove selectivity, semi-intercalation and chiral recognition

Area of Science:

• Supramolecular Chemistry
• Biophysical Chemistry
• Molecular Interactions

Background:

• Understanding DNA-ligand interactions is crucial for developing novel therapeutic agents.
• Helicene derivatives are explored for their unique structural and photophysical properties.
• The interaction of small molecules with DNA can modulate gene expression and cellular processes.

Purpose of the Study:

• To investigate the binding modes of a water-soluble [6]helicene derivative (1) with double-stranded DNA (dsDNA).
• To elucidate the role of the imidazole ring and side chain in the DNA binding process.
• To determine the specificity of binding towards different DNA forms and bases.

Main Methods:

• Electrochemical and electrophoretic techniques.
• Spectroscopic methods including UV Resonance Raman (UVRR) spectroscopy.
• Computational approaches: molecular dynamics (MD) and quantum mechanical calculations.
• Circular dichroism (CD) spectroscopy and isothermal titration calorimetry (ITC) for enantiomer studies.

Main Results:

• Experimental and theoretical data confirmed minor groove binding of compound 1 to dsDNA.
• The positively charged imidazole ring and hydrophobic side chain facilitate DNA accommodation.
• No intercalation into duplex DNA or stable binding to single-stranded DNA was observed.
• Optically pure enantiomers ((P)-1 and (M)-1) showed specific binding preferences.
• Compound 1 preferentially interacts with adenine (A) and guanine (G) bases within dsDNA.

Conclusions:

• The [6]helicene derivative 1 exhibits minor groove binding to dsDNA, with contributions from its charged and hydrophobic moieties.
• The study provides insights into the molecular basis of helicene-DNA interactions.
• Compound 1 demonstrates potential as a DNA-interacting agent, with specific base preferences.