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

doi:10.6023/A15030204

Acta Chim. Sinica ›› 2015, Vol. 73 ›› Issue (8): 765-769.DOI: 10.6023/A15030204 Previous Articles Next Articles

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一类非同寻常的二次Lossen重排反应:异羟肟酸的新型解毒分子作用机制

朱本占, 邵波, 李锋, 刘玉祥, 黄春华

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北京 100085

投稿日期:2015-03-25 发布日期:2015-07-07
通讯作者: 朱本占 E-mail:bzhu@rcees.ac.cn
基金资助:
项目受中国科学院战略性先导科技专项(B类) (XDB01020300)和国家自然科学基金(Nos. 21237005, 21321004, 20925724)资助.

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

Zhu Benzhan, Shao Bo, Li Feng, Liu Yuxiang, Huang Chunhua

State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China

Received:2015-03-25 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.

Key words: Lossen rearrangement, tetrachloro-1,4-benzoquinone, hydroxamic acids, 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone, hydrolysis

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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 Chim. Sinica, 2015, 73(8): 765-769.

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[1] Bolton, J. L.; Trush, M. A.; Penning, T. M.; Dryhurst, G.; Monks, T. J. Chem. Res. Toxicol. 2000, 13, 135.
[2] Song, Y.; Wagner, B. A.; Witmer, J. R.; Lehmler, H. J.; Buettner, G. R. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 9725.
[3] Zhu, B. Z.; Shan, G. Q. Chem. Res. Toxicol. 2009, 22, 969.
[4] Meunier, B. Science 2002, 296, 270.
[5] Gupta, S. S.; Stadler, M.; Noser, C. A.; Ghosh, A.; Steinhoff, B.; Lenoir, D.; Horwitz, C. P.; Schramm, K. W.; Collins, T. J. Science 2002, 296, 326.
[6] Sorokin, A.; Seris, J. L.; Meunier, B. Science 1995, 268, 1163.
[7] Manderville, R. A.; Pfohl-Leszkowicz, A. Advances Molecular Toxicology, Elsevier, Amsterdam, 2006, pp. 85~138.
[8] Yu, Y.; Wong, J.; Lovejoy, D. B.; Kalinowski, D. S.; Richardson, D. R. Clin. Cancer Res. 2006, 12, 6876.
[9] Marks, P. A.; Breslow, R. Nat. Biotechnol. 2007, 25, 84.
[10] Li, N. N.; Zhao, D.; Kirschbaum, M.; Zhang, C.; Lin, C. L.; Todorov, I.; Kandeel, F.; Forman, S.; Zeng, D. F. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 4796.
[11] Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M. L.; Rehman, M.; Walther, T. C.; Olsen, J. V.; Mann, M. Science 2009, 325, 834.
[12] Zhu, B. Z.; Har-El, R.; Kitrossky, N.; Chevion, M. Free Radic. Biol. Med. 1998, 24, 360.
[13] Witte, I.; Zhu, B. Z.; Lueken, A.; Magnani, D.; Stossberg, H.; Chevion, M. Free Radic. Biol. Med. 2000, 28, 693.
[14] Zhu, B. Z.; Zhao, H. T.; Kalyanaraman, B.; Frei, B. Free Radical Biol. Med. 2002, 32, 465.
[15] Zhu, B. Z.; Kalyanaraman, B.; Jiang, G. B. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 17575.
[16] Zhu, B. Z.; Zhao, H. T.; Kalyanaraman, B.; Liu, J.; Shan, G. Q.; Du, Y. G.; Frei, B. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 3698.
[17] Zhu, B. Z.; Shan, G. Q.; Huang, C. H.; Kalyanaraman, B.; Mao, L.; Du, Y. G. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 11466.
[18] Zhu, B. Z.; Zhu, J. G.; Mao, L.; Kalyanaraman, B.; Shan, G. Q. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20686.
[19] Sarr, D. H.; Kazunga, C.; Charles, M. J.; Pavlovich, J. G.; Aitken, M. D. Environ. Sci. Technol. 1995, 29, 2735.
[20] Johnson, J. E.; Riesgo, E. C.; Jano, I. J. Org. Chem. 1996, 61, 45.
[21] Orth, E. S.; da Silva, P. L. F.; Mello, R. S.; Bunton, C. A.; Milagre, H. M. S.; Eberlin, M. N.; Fiedler, H. D.; Nome, F. J. Org. Chem. 2009, 74, 5011.
[22] Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376.
[23] Pereira, M. M. A.; Santos, P. P. The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids, John Wiley & Sons Ltd., Chichester, 2009, pp. 343～499.
[24] Dube, P.; Nathel, N. F.; Vetelino, M.; Couturier, M.; Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Org. Lett. 2009, 11, 5622.
[25] Chignell, C. F.; Han, S. K.; Moulthys-Mickalad, A.; Sik, R. H.; Stadler, K.; Kadiiska, M. B. Toxicol. Appl. Pharmacol. 2008, 230, 17.
[26] Teuten, E. L.; Xu, L.; Reddy, C. M. Science 2005, 307, 917.
[27] Kelly, B. C.; Ikonomou, M. G.; Blair, J. D.; Morin, A. E.; Gobas, F. A P C. Science 2007, 317, 236.
[28] Zhao, Y. L.; Qin, F.; Boyd, J. M.; Anichina, J.; Li, X. F. Anal. Chem. 2010, 82, 4599.
[29] Decalmanovici, R. W.; Billi, S. C.; Aldonatti, C. A.; Deviale, L. C. S. M. Biochem. Pharmacol. 1986, 35: 2399.
[30] Bromberg, L.; Schreuder-Gibson, H.; Creasy, W. R.; McGarvey, D. J.; Fry, R. A.; Hatton, T. A. Ind. Eng. Chem. Res. 2009, 48, 1650.
[31] Morad, Y.; Banin, E.; Averbukh, E.; Berenshtein, E.; Obolensky, A.; Chevion, M. Invest. Ophthalmol. Vis. Sci. 2005, 46, 1640.

一类非同寻常的二次Lossen重排反应:异羟肟酸的新型解毒分子作用机制

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

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