Novel isoxazole polycyclic aromatic hydrocarbons as DNA-intercalating agents

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Molecular Biology

Background:

• Development of novel DNA-intercalating agents for remote tumor targeting.
• Isoxazole polycyclic aromatic hydrocarbons represent a promising class of compounds.

Purpose of the Study:

• Synthesize and characterize new isoxazole polycyclic aromatic hydrocarbons.
• Evaluate their in vitro cytotoxic activity against cancer cells.
• Investigate their DNA binding and intercalation mechanisms.

Main Methods:

• 1,3-dipolar cycloaddition for synthesis.
• NOE experiments and PM3 computational studies for structural determination.
• In vitro cytotoxicity assays (IC50 determination).
• DNA binding studies (binding constants) and docking simulations.

Main Results:

• Successful synthesis of third-generation isoxazole polycyclic aromatic hydrocarbons with good yields.
• Compound 7d exhibited potent in vitro cytotoxic activity (IC50 = 4 μM) against A-549 human lung cancer cells.
• Compound 7d demonstrated significant DNA intercalation binding constants (up to 1.7 × 10^5 M⁻¹), with a preference for AT-rich regions.

Conclusions:

• The synthesized isoxazole derivatives effectively act as DNA intercalators.
• Compound 7d shows potential as a lead compound for lung cancer therapy.
• These compounds interact with DNA via intercalation, primarily targeting AT base pairs through the minor groove.