Photosensitization of Guanine-Specific DNA Damage by a Cyano-Substituted Quinoxaline Di-N-oxide

Abstract

The cyano-substituted quinoxaline di-N-oxide (2) is a potential antitumor agent, 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'-deoxyguanosine positions upon irradiation in the UV-A (lambda(max) = 350 nm) region. Strand damage is induced in single-stranded and double-stranded substrates, 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 molecule 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 ambiguous and indicate that commonly used experimental tests for this species may be less definitive than often thought. The involvement of other reactive oxygen species in strand damage, such as hydroxyl radical, is ruled out.

Photosensitization of DNA damage by glycated proteins

“…However, azide and DABCO are also quenchers of photoexcited states of various sensitizers. 41 Moreover, -histidine 42 and azide 43 are effective scavengers of hydroxyl radicals and consequently, their use as specific probes for the involvement of singlet oxygen is limited. Remarkably, the thiol compounds -penicillamine, N-acetyl-cysteine (NAC), and glutathione (GSH) were fully protective.…”

Synthesis and Crystal Structure of the Azoxydichinyl Helicene, Pyrido[3,2-f]quinolino[6,5-c]cinnoline 5-Oxide Monohydrate

“…[1–4] During the course of recent studies on the enzymatic metabolism of 6-nit roquinoline, we observed formation of an unexpected product when 6-hydroxylaminoquinoline ( 1 , Scheme 1) was treated with xanthine oxidase or when 6-nitroquinoline ( 2 ) was treated with NADPH:cytochrome P450 reductase and NADPH under anaerobic conditions. Characterization of the molecule by NMR, high resolution mass spectrometry, and X-ray crystallography revealed this product to be the helicene, pyrido[3,2- f ]quinolino[6,5- c ]cinnoline 5-oxide ( 3 ).…”

Synthesis, Crystal Structure, and Rotational Energy Profile of 3-Cyclopropyl-1,2,4-benzotriazine 1,4-Di-N-oxide

“…21 The solvent was then evaporated and the residue purified using gravity column chromatography on silica gel eluted with ethyl acetate-hexanes (1:1) to provide a 10–15% yield of 3 as deep yellow powder. 1 H-NMR (CDCl 3 , 500 MHz): δ 8.55 (dd, J = 8.5, 1 Hz, 1H), 8.43 (dd, J = 8.5, 1 Hz, 1H), 8.00 (ddd, J = 8.5, 7, 1 Hz, 1H), 7.79 (ddd, J = 8.5, 7, 1 Hz, 1H), 3.14 (tt, J = 8.0, 5.0 Hz, 1H), 1.36 (m, 4H); 13 C-NMR (125 MHz, CDCl 3 ): δ 157.1, 139.0, 135.4, 133.9, 131.1, 121.5, 119.4, 10.1, 9.3; HRMS (ESI) m/z calc for C 10 H 10 N 3 O 2 (M+H + ) 204.0773, found 204.0765.…”