A Photoinducible DNA Cross-Linking Agent with Potent Cytotoxicity and Selectivity Toward Triple-Negative Breast...

Area of Science:

• Medicinal Chemistry
• Photochemistry
• Molecular Biology

Background:

• DNA interstrand cross-links (ICLs) are critical cytotoxic mechanisms for anticancer drugs.
• Selenium compounds are promising anticancer agents.
• Developing photoresponsive anticancer drugs offers targeted therapy potential.

Purpose of the Study:

• To synthesize and evaluate a novel binaphthalene analog containing a phenyl selenide leaving group for its photochemical reactivity, DNA cross-linking ability, and selective cytotoxicity.
• To investigate the mechanism of photoinduced DNA damage and cellular response.

Main Methods:

• Synthesis of binaphthalene analog 1.
• Photochemical reactivity studies with DNA.
• DNA interstrand cross-linking and monoalkylation assays.
• Cytotoxicity assays (IC50 determination) on cancer and normal cells.
• Alkaline comet assay for DNA damage assessment.
• Glutathione (GSH) level analysis.

Main Results:

• Compound 1 exhibits photoresponsive DNA interstrand cross-linking upon UV irradiation, forming ~15% ICL products.
• The cross-linking process involves free radicals and carbocations and is sequence-dependent, primarily targeting dG/dC pairs.
• Compound 1 shows significant photoenhanced cytotoxicity against cancer cells (IC50 = 1.7 μM) but not normal cells.
• Normal cells possess higher GSH levels and efficient DNA repair mechanisms, contributing to selective toxicity.

Conclusions:

• The synthesized binaphthalene analog 1 acts as a photoactivatable prodrug for targeted DNA interstrand cross-linking.
• The compound demonstrates selective cytotoxicity towards triple-negative breast cancer cells, mediated by photoinduced DNA damage and differential cellular defense mechanisms.
• This photoresponsive selenium compound holds potential for developing targeted cancer therapies.