State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20686-90. doi: 10.1073/pnas.1010950107. Epub 2010 Nov 12.
Hydroxamic acids, which are best-known for their metal-chelating properties in biomedical research, have been found to effectively detoxify the carcinogenic polyhalogenated quinoid metabolites of pentachlorophenol and other persistent organic pollutants. However, the chemical mechanism underlying such detoxication is unclear. Here we show that benzohydroxamic acid (BHA) could dramatically accelerate the conversion of the highly toxic tetrachloro-1, 4-benzoquinone (p-chloranil) to the much less toxic 2,5-dichloro-3, 6-dihydroxy-1, 4-benzoquonine (chloranilic acid), with rate accelerations of up to 150,000-fold. In contrast, no enhancing effect was observed with O-methyl BHA. The major reaction product of BHA was isolated and identified as O-phenylcarbamyl benzohydroxamate. On the basis of these data and oxygen-18 isotope-labeling studies, we proposed that suicidal nucleophilic attack coupled with an unexpected double Lossen rearrangement reaction was responsible for this remarkable acceleration of the detoxication reaction. This is the first report of an unusually mild and facile Lossen-type rearrangement, which could take place under normal physiological conditions in two consecutive steps. Our findings may have broad biological and environmental implications for future research on hydroxamic acids and polyhalogenated quinoid carcinogens, which are two important classes of compounds of major biomedical and environmental interest.
羟肟酸以其在生物医学研究中对金属的螯合特性而闻名，现已被发现可有效解毒五氯苯酚和其他持久性有机污染物的致癌多卤代醌类代谢物。然而，这种解毒的化学机制尚不清楚。在这里，我们表明苯羟肟酸（BHA）可以显著加速高毒性的四氯-1,4-苯醌（对氯苯醌）向毒性较小的 2,5-二氯-3,6-二羟基-1,4-苯醌（氯苯醌）的转化，其加速倍数高达 150,000 倍。相比之下，O-甲基 BHA 没有增强作用。BHA 的主要反应产物被分离并鉴定为 O-苯甲酰基苯羟肟酸。基于这些数据和氧-18 同位素标记研究，我们提出自杀亲核攻击加上意外的双 Lossen 重排反应是导致这种解毒反应显著加速的原因。这是首例报道的异常温和且简单的 Lossen 型重排反应，它可以在两个连续步骤中在正常生理条件下发生。我们的发现可能对未来关于羟肟酸和多卤代醌类致癌剂的研究具有广泛的生物学和环境意义，它们是两类具有重要生物医学和环境意义的重要化合物。
