A Photoinducible\nDNA Cross-Linking Agent with Potent\nCytotoxicity and Selectivity Toward Triple-Negative Breast Cancer\nCell Line

DNA\ninterstrand cross-links (ICLs) are the sources of the cytotoxicity\nof many anticancer agents. Selenium compounds showed great potential\nas anticancer drugs. In this work, we synthesized a binaphthalene\nanalog <b>1</b> containing phenyl selenide (−SePh) as\nthe leaving group and investigated its photochemical reactivity toward\nDNA as well as its cytotoxicity and selectivity. DNA ICLs were not\nobserved with binaphthalene phenyl selenide <b>1</b> without\nUV irradiation, while ∼15% DNA ICL products were detected with\nUV irradiation, indicating a photoresponsive property of <b>1</b>. The trapping reactions with TEMPO and MeONH<sub>2</sub>, respectively,\nsuggested that free radicals and carbocations are involved in the\nDNA cross-linking process induced by the photoirradiation of <b>1</b>. The photochemical reactivity of <b>1</b> toward DNA\nwas sequence-dependent. DNA interstrand cross-linking occurred mainly\nat dG/dC base pairs, while monoalkylations occurred at dGs and dAs.\nAdditionally, we have demonstrated that <b>1</b> alone without\nUV irradiation did not inhibit cancer cell growth even with a concentration\nof 100 μM, while the cytotoxicity of <b>1</b> toward cancer\ncells was significantly enhanced upon 350 nm irradiation with an IC<sub>50</sub> of 1.7 μM. No cytotoxicity was observed toward normal\nepithelial MCF 10A cells, regardless of UV exposure, in the presence\nor absence of <b>1</b>. The alkaline comet assay suggested that\nthe photoinduced cytotoxicity of <b>1</b> is correlated to cellular\nDNA damage. Normal cells showed higher levels of GSH than cancer cells\nand exhibited efficient DNA repair mechanisms, which can both prevent\nand repair potential DNA damage induced by <b>1</b>, contributing\nto the selective cytotoxicity of the prodrug toward triple-negative\nbreast cancer cells.