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Detoxifying carcinogenic polyhalogenated quinones by hydroxamic acids via an unusual double Lossen rearrangement mechanism

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 su... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America 30 November 2010, Vol.107(48), pp.20686-20690
Main Author: Zhu, Ben-Zhan
Other Authors: Zhu, Jun-Ge , Mao, Li , Kalyanaraman, Balaraman , Shan, Guo-Qiang , Halpern, Jack
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 00278424
Link: https://www.jstor.org/stable/25756764
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title: Detoxifying carcinogenic polyhalogenated quinones by hydroxamic acids via an unusual double Lossen rearrangement mechanism
format: Article
creator:
  • Zhu, Ben-Zhan
  • Zhu, Jun-Ge
  • Mao, Li
  • Kalyanaraman, Balaraman
  • Shan, Guo-Qiang
  • Halpern, Jack
subjects:
  • Physical sciences -- Chemistry -- Chemical reactions
  • Physical sciences -- Chemistry -- Chemical compounds
  • Physical sciences -- Chemistry -- Chemical compounds
  • Physical sciences -- Chemistry -- Chemical compounds
  • Biological sciences -- Biology -- Anatomy
  • Physical sciences -- Physics -- Microphysics
  • Physical sciences -- Chemistry -- Chemical compounds
  • Physical sciences -- Chemistry -- Chemical compounds
  • Health sciences -- Medical conditions -- Diseases
  • Physical sciences -- Chemistry -- Chemical reactions
ispartof: Proceedings of the National Academy of Sciences of the United States of America, 30 November 2010, Vol.107(48), pp.20686-20690
description: 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.
language: eng
source:
identifier: ISSN: 00278424
fulltext: fulltext
issn:
  • 0027-8424
  • 00278424
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titleDetoxifying carcinogenic polyhalogenated quinones by hydroxamic acids via an unusual double Lossen rearrangement mechanism
creatorZhu, Ben-Zhan ; Zhu, Jun-Ge ; Mao, Li ; Kalyanaraman, Balaraman ; Shan, Guo-Qiang ; Halpern, Jack
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subjectPhysical sciences -- Chemistry -- Chemical reactions ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Anatomy ; Physical sciences -- Physics -- Microphysics ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical compounds ; Health sciences -- Medical conditions -- Diseases ; Physical sciences -- Chemistry -- Chemical reactions
descriptionHydroxamic 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.
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titleDetoxifying carcinogenic polyhalogenated quinones by hydroxamic acids via an unusual double Lossen rearrangement mechanism
descriptionHydroxamic 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.
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abstractHydroxamic 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.
pubNational Academy of Sciences
doi10.1073/pnas.1010950107
eissn10916490
date2010-11-30