Abstract
DNA interstrand cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. Selenium compounds showed great potential as anticancer drugs. In this work, we synthesized a binaphthalene analog 1 containing phenyl selenide (-SePh) as the leaving group and investigated its photochemical reactivity toward DNA as well as its cytotoxicity and selectivity. DNA ICLs were not observed with binaphthalene phenyl selenide 1 without UV irradiation, while ∼15% DNA ICL products were detected with UV irradiation, indicating a photoresponsive property of 1. The trapping reactions with TEMPO and MeONH2, respectively, suggested that free radicals and carbocations are involved in the DNA cross-linking process induced by the photoirradiation of 1. The photochemical reactivity of 1 toward DNA was sequence-dependent. DNA interstrand cross-linking occurred mainly at dG/dC base pairs, while monoalkylations occurred at dGs and dAs. Additionally, we have demonstrated that 1 alone without UV irradiation did not inhibit cancer cell growth even with a concentration of 100 μM, while the cytotoxicity of 1 toward cancer cells was significantly enhanced upon 350 nm irradiation with an IC50 of 1.7 μM. No cytotoxicity was observed toward normal epithelial MCF 10A cells, regardless of UV exposure, in the presence or absence of 1. The alkaline comet assay suggested that the photoinduced cytotoxicity of 1 is correlated to cellular DNA damage. Normal cells showed higher levels of GSH than cancer cells and exhibited efficient DNA repair mechanisms, which can both prevent and repair potential DNA damage induced by 1, contributing to the selective cytotoxicity of the prodrug toward triple-negative breast cancer cells.