Photosensitization of guanine-specific DNA damage by a cyano-substituted quinoxaline di-N-oxide
Photosensitization of guanine-specific DNA damage by a cyano-substituted quinoxaline di-N-oxide
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DOI：
10.1021/tx990149s
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发表时间：
1999-12-01
影响因子：
4.1
通讯作者：
Greenberg, MM
中科院分区：
文献类型：
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作者：
Fuchs, T;Gates, KS;Greenberg, MM
氰基取代的喹喔啉二-N-氧化物（2）是一种潜在的抗肿瘤药物，它选择性地杀死缺氧细胞。在研究这种药物在DNA损伤过程中作为O-2替代物的潜在能力时，我们发现2在UV-A（λ（max）= 350 nm）区域照射后选择性地在2 '-脱氧鸟苷位置产生碱不稳定损伤。链损伤在单链和双链底物中诱导，后者对损伤形成稍微更敏感。碱性不稳定病变在有氧和厌氧条件下形成。碱不稳定性病变的有效形成2表明，这种分子可能表现出光毒性。随后对这一过程的研究表明，光激发2通过I型过程破坏DNA。旨在确定单线态O-2参与的实验结果是模糊的，并表明该物种常用的实验测试可能不如通常认为的那样确定。其他活性氧参与链损伤，如羟基自由基，被排除在外。
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.