An Unusual Double Lossen Rearrangement Reaction: The Novel Molecular Detoxication Mechanism for Hydroxamic Acids
Received date: 2015-03-25
Online published: 2015-07-07
Supported by
Project supported by the Strategic Priority Research Program of CAS (Grant No. XDB01020300) and the National Natural Science Foundation of China (Nos. 21237005, 21321004, 20925724).
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 nucleophilic 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.
Zhu Benzhan , Shao Bo , Li Feng , Liu Yuxiang , Huang Chunhua . An Unusual Double Lossen Rearrangement Reaction: The Novel Molecular Detoxication Mechanism for Hydroxamic Acids[J]. Acta Chimica Sinica, 2015 , 73(8) : 765 -769 . DOI: 10.6023/A15030204
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