Photosensitization of guanine-specific DNA damage by a cyano-substituted quinoxaline di-N-oxide

The cyano-substituted quinoxaline di-N-oxide (2) is a potential antitumor a gent, which selectively kills hypoxic cells. While investigating this drug' s potential ability to act as a surrogate for O-2 in DNA damage processes, we discovered that 2 produces alkali-labile lesions selectively at 2'-deoxy guanosine positions upon irradiation in the UV-A (lambda(max) = 350 nm) reg ion. Strand damage is induced in single-stranded and double-stranded substr ates, with the latter being slightly more susceptible to lesion formation. Alkaline-labile lesions are formed under aerobic and anaerobic conditions. The efficient formation of alkali-labile lesions by 2 suggests that this mo lecule may exhibit phototoxicity. Subsequent investigation of this process suggests that photoexcited 2 damages DNA via a type I process. The results of experiments aimed at determining the involvement of singlet O-2 are ambi guous and indicate that commonly used experimental tests for this species m ay be less definitive than often thought. The involvement of other reactive oxygen species in strand damage, such as hydroxyl radical, is ruled out.