An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl 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 unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids
	Zhu, Ben-Zhan; Xu, Dan; Qin, Li; Huang, Chun-Hua; Xie, Lin-Na; Mao, Li; Shao, Jie; Kalyanaraman, Balaraman
刊名	FREE RADICAL BIOLOGY AND MEDICINE
	2020-01
卷号	146 页码:150-159
关键词	N-centered amidyl radical Nitroxide radical Hydrogen-abstraction Tetrachloroquinoid compounds N-alkyl hydroxamic acids
ISSN号	0891-5849
英文摘要	We found previously that nitroxide radical of desferrioxamine (DFO center dot) could be produced from the interaction between the classic iron chelating agent desferrioxamine (DFO, an N-alkyl trihydroxamic acid) and tetrachlorohydroquinone (TCHQ), one of the carconogenic quinoind metabolites of the widely used wood preservative pentachlorophenol. However, the underlying molecular mechanism remains unclear. Here N-methylacetohydroxamic acid ( N-MeAHA) was synthesized and used as a simple model compound of DFO for further mechanistic study. As expected, direct ESR studies showed that nitroxide radical of N-MeAHA (Ac-(CH3)NO center dot) can be produced from N-MeAHA/TCHQ. Interestingly and unexpectedly, when TCHQ was substituted by its oxidation product tetrachloro-1,4-benzoquinone (TCBQ), although Ac-(CH3)NO center dot could also be produced, no concurrent formation of tetrachlorosemiquinone radical (TCSQ(center dot)) and TCHQ was detected, suggesting that Ac-(CH3) NO center dot did not result from direct oxidation of N-MeAHA by TCSQ(center dot) or TCBQ as proposed previously. To our surprise, a new nitrogen-centered amidyl radical was found to be generated from N-MeAHA/TCBQ, which was observed by ESR with the spin-trapping agents and further unequivacally identified as Ac-(CH3)N-center dot by HPLC-MS. The final product of amidyl radical was isolated and identified as its corresponding amine. Analogous radical homolysis mechanism was observed with other halogenated quinoid compounds and N-alkyl hydroxamic acids including DFO. Interestingly, amidyl radicals were found to induce both DNA strand breaks and DNA adduct formation, suggesting that N-alkyl hydroxamic acids may exert their potential side-toxic effects via forming the reactive amidyl radical species. This study represents the first report of an unexpected new pathway for nitroxide radical production via hydrogen abstration reaction of a more reactive amidyl radical intermediate during the detoxification of the carcinogenic polyhalogenated quinones by N-alkyl hydroxamic acids, which provides more direct experimental evidence to better explain not only our previous finding that excess DFO can provide effective but only partial protection against TCHQ (or TCBQ)-induced biological damage, and also the potential side-toxic effects induced by DFO and other N-alkyl hydroxamic acid drugs.
内容类型	期刊论文
源URL	[http://ir.rcees.ac.cn/handle/311016/44601]
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, Ben-Zhan,Xu, Dan,Qin, Li,et al. An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids[J]. FREE RADICAL BIOLOGY AND MEDICINE,2020,146:150-159.
APA	Zhu, Ben-Zhan.,Xu, Dan.,Qin, Li.,Huang, Chun-Hua.,Xie, Lin-Na.,...&Kalyanaraman, Balaraman.(2020).An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids.FREE RADICAL BIOLOGY AND MEDICINE,146,150-159.
MLA	Zhu, Ben-Zhan,et al."An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids".FREE RADICAL BIOLOGY AND MEDICINE 146(2020):150-159.