An Unusual Double Lossen Rearrangement Reaction: The Novel Molecular Detoxication Mechanism for Hydroxamic Acids

CORC > 生态环境研究中心 > 中国科学院生态环境研究中心 > 环境化学与生态毒理学国家重点实验室

	An Unusual Double Lossen Rearrangement Reaction: The Novel Molecular Detoxication Mechanism for Hydroxamic Acids
	Zhu Benzhan; Shao Bo; Li Feng; Liu Yuxiang; Huang Chunhua
刊名	ACTA CHIMICA SINICA
	2015-08-15
卷号	73 期号:8 页码:765-769
关键词	Lossen rearrangement tetrachloro-1 hydroxamic acids 2 hydrolysis 4-benzoquinone 5-dichloro-3 6-dihydroxy-1 4-benzoquinone
英文摘要	Hydroxamic acids have attracted considerable interest recently because of their capacity to inhibit a variety of enzymes such as metalloproteases and lipoxygenase, and transition metal mediated oxidative stress. In our previous work, we found that deferoxamine (a trihydroxamate iron chelator used for the treatment of iron overload diseases) and other hydroxamic acids, but not the classic iron chelating agents such as diethylenetriaminepentaacetic acid (DTPA), could effectively detoxify the carcinogenic polyhalogenated quinoid metabolites of pentachlorophenol. However, the chemical mechanism underlying such detoxication is not clear. We found that benzohydroxamic acid (BHA, a model hydroxamic acid) could dramatically accelerate the hydrolysis of the highly toxic tetrachloro-1,4-benzoquinone (TCBQ) to its much less toxic product, 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (DDBQ), with rate accelerations of up to 150000-fold. No enhancing effect was observed with O-methyl BHA, suggesting free benzohydroxamate anion is essential for the acceleration of TCBQ hydrolysis. The major reaction product of BHA was isolated and identified as O-phenylcarbamyl benzohydroxamate. Based on these data and oxygen-18 isotope-labelling 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: A nudeophilic reaction takes place between the benzohydroxamate anion (ArC(O)-NH-O-) and TCBQ, first forming an unstable transient intermediate ArC(O)-NH-O-trichloro-1,4-benzoquinone. Following loss of a proton from nitrogen to form the anionic ArC(O)-N--O-trichloro-1,4-benzoquinone intermediate, a spontaneous Lossen-type rearrangement leads to the formation of TrCBQ-O- (at low BHA/TCBQ molar ratios) and phenyl isocyanate. When BHA is in excess, TrCBQ-O- further reacts with BHA, through a similar reaction intermediate, and a second-step spontaneous Lossen-type rearrangement reaction yields DDBQ and another molecule of phenyl isocyanate. The phenyl isocyanate could react with another molecule of BHA to yield O-phenylcarbamyl benzohydroxamate. 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 hydroxamate pharmaceuticals and polyhalogenated quinoid carcinogens, which are two important classes of compounds of major biomedical and environmental interest.
研究领域[WOS]	Chemistry, Multidisciplinary
WOS记录号	WOS:000361850600001
公开日期	2016-03-15
内容类型	期刊论文
源URL	[http://ir.rcees.ac.cn/handle/311016/32513]
专题	生态环境研究中心_环境化学与生态毒理学国家重点实验室
推荐引用方式 GB/T 7714	Zhu Benzhan,Shao Bo,Li Feng,et al. An Unusual Double Lossen Rearrangement Reaction: The Novel Molecular Detoxication Mechanism for Hydroxamic Acids[J]. ACTA CHIMICA SINICA,2015,73(8):765-769.
APA	Zhu Benzhan,Shao Bo,Li Feng,Liu Yuxiang,&Huang Chunhua.(2015).An Unusual Double Lossen Rearrangement Reaction: The Novel Molecular Detoxication Mechanism for Hydroxamic Acids.ACTA CHIMICA SINICA,73(8),765-769.
MLA	Zhu Benzhan,et al."An Unusual Double Lossen Rearrangement Reaction: The Novel Molecular Detoxication Mechanism for Hydroxamic Acids".ACTA CHIMICA SINICA 73.8(2015):765-769.