Design, Synthesis, and Characterization of Binaphthalene Precursors as Photoactivated DNA Interstrand Cross-Linkers.

Most recently, alkylation via photogenerated carbocations has been identified as a novel mechanism for photoinduced DNA interstrand cross-link (ICL) formation by bifunctional aryl compounds. However, most compounds showed a low efficiency for DNA cross-linking. Here, we have developed a series of new 1,1'-binaphthalene analogues that efficiently form DNA ICLs upon 350 nm irradiation via generated 2-naphthalenylmethyl cations. The DNA cross-linking efficiency depends on the substituents at position 4 of the naphthalene moiety as well as the leaving groups. Compounds with NO, Ph, H, Br, or OMe substituents led to 2-4 times higher DNA ICL yields than those with a boronate ester group. Compounds with trimethylammonium salt as a leaving group showed slightly better cross-linking efficiency than those with bromo as a leaving group. Some of these compounds showed a better cross-linking efficiency than that of traditional alkylating agents, such as nitrogen mustard analogues or quinone methide precursors. These highly efficient photoactivated carbocation precursors allow determination and characterization of the adducts formed between the photogenerated naphthalenyl cations and four natural nucleosides, indicating that the alkylation sites for these naphthalene analogues are dG, dA, and dC.