Photoinduced DNA Interstrand Cross-Linking by Benzene Derivatives: Leaving Groups Determine the Efficiency of the Cross-Linker.

We have synthesized and characterized two small libraries of 2-OMe or 2-NO2-benzene analogues 2a-i and 3a-i containing a wide variety of leaving groups. Irradiation of these compounds at 350 nm generated benzyl radicals that were spontaneously oxidized to benzyl cations directly producing DNA interstrand cross-links (ICLs). Compounds with a 2-methoxy substituent showed a faster cross-linking reaction rate and higher ICL efficiency than the corresponding 2-nitro analogues. Apart from the aromatic substituent, the benzylic leaving groups greatly affected DNA cross-linking efficiency. Higher ICL yields were observed for compounds with OCH3 (3b), OCH2Ph (3d), or Ph3P+ (3i) as leaving groups than those containing OAc (3a), NMe2 (3e), morpholine (3f), OCH2CH═CH2 (3c), SPh (3g), or SePh (3h). The heat stability study of the isolated ICL products indicated that dGs were the preferred alkylation sites in DNA for the benzyl cations produced from 2a-i, 3c, and 3e-i while 3a (L = OAc), 3b (L = OMe), and 3d (L = OCH2Ph) showed a similar photoreactivity toward dGs and dAs. Although the photogenerated benzyl cations alkylated dG, dC, and dA, ICL assay with variation of DNA sequences showed that the ICL reaction occurred with opposing dG/dC but not with staggered dA/dA.