Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location.,Free Radical Biology and Medicine

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Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2019-07-15 , DOI: 10.1016/j.freeradbiomed.2019.07.012
Li Qin ₁ , Chun-Hua Huang ₁ , Dan Xu ₁ , Lin-Na Xie ₂ , Jie Shao ₁ , Li Mao ₁ , Balaraman Kalyanaraman ₃ , Ben-Zhan Zhu ₄

Affiliation

Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl radical, which was considered to be responsible for its anti-tuberculosis activity. However, it is still not clear whether the previously-proposed N-centered isoniazidyl radical intermediate can be initially produced or not; and if so, what is its exact location on the hydrazine group, distal- or proximal-nitrogen? Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the characteristic and transient N-centered isoniazidyl radical intermediate can be detected and identified from INH activation uniquely by Mn(III)Acetate not by Mn(III) pyrophosphate. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by 15N-isotope-labeling techniques via using 15N-labeled INH. Diisonicotinyl hydrazine was identified as a new reaction product from INH/Mn(III). Analogous results were observed with other hydrazides. This study represents the first detection and unequivocal identification of the initial N-centered isoniazidyl radical and its exact location. These findings should provide a new perspective on the molecular mechanism of INH activation, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.

中文翻译：

Mn（III）激活抗结核药物异烟肼的分子机制：关键的以N为中心的异烟肼基自由基及其确切位置的首次检测和明确鉴定。

异烟肼（INH）是使用最广泛的抗结核药物，已被Mn（III）激活以产生以活性碳为中心的异烟酸酰基自由基，这被认为是其抗结核活性的原因。但是，尚不清楚是否可以首先制备先前提出的N-中心的异烟肼基自由基中间体。如果是的话，它在肼基，远端氮或近端氮上的确切位置是什么？通过ESR旋转捕集和HPLC / MS方法的互补应用，我们在此表明，可以通过乙酸（而不是焦磷酸锰（III））独特地从INH活化中检测和鉴定特征性和短暂的以N为中心的异烟肼基自由基中间体。。通过使用15N标记的INH通过15N同位素标记技术，发现自由基的确切位置在肼基团的末端氮上。二异烟碱基肼被鉴定为来自INH / Mn（III）的新反应产物。用其他酰肼观察到相似的结果。这项研究代表了对最初以N为中心的异烟肼基自由基及其确切位置的首次检测和明确鉴定。这些发现应为INH激活的分子机制提供一个新的观点，这可能对未来研究更有效的酰肼抗结核药物具有广泛的生物医学和毒理学意义。用其他酰肼观察到相似的结果。这项研究代表了对最初以N为中心的异烟肼基自由基及其确切位置的首次检测和明确鉴定。这些发现应为INH激活的分子机制提供一个新的观点，这可能对未来研究更有效的酰肼抗结核药物具有广泛的生物医学和毒理学意义。用其他酰肼观察到相似的结果。这项研究代表了对最初以N为中心的异烟肼基自由基及其确切位置的首次检测和明确鉴定。这些发现应为INH激活的分子机制提供一个新的观点，这可能对未来研究更有效的酰肼抗结核药物具有广泛的生物医学和毒理学意义。

更新日期：2019-07-16

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