7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide.
7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide.
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DOI：
10.1007/s00204-012-0872-9
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发表时间：
2012-10
影响因子：
6.1
通讯作者：
Sartorelli, Alan C.
中科院分区：
文献类型：
--
作者：
Patridge, Eric V.;Eriksson, Emma S. E.;Penketh, Philip G.;Baumann, Raymond P.;Zhu, Rui;Shyam, Krishnamurthy;Eriksson, Leif A.;Sartorelli, Alan C.
在这里，我们报道了 7-硝基-4-（苯硫基）苯并呋喃 (NBF-SPh)，它是一组专利抗癌 7-硝基苯并呋喃 (NBF) 中最有效的衍生物，已被认为通过扰乱蛋白质-蛋白质相互作用发挥作用。我们证明 NBF-SPh 参与有毒的氧化还原循环，在分子氧存在的情况下快速产生活性氧 (ROS)，这是第一份详细介绍任何抗癌 NBF 的 ROS 产生的报告。氧描计研究表明，NBF-SPh 消耗分子氧的速度相当快，甚至可以与白花丹素、甲萘醌和胡桃醌相媲美。生化和酶测定确定超氧化物和过氧化氢是其氧化还原循环活性的产物，并且 ROS 产生的快速速率似乎足以解释 NBF-SPh (LC50 = 12.1 µM) 的部分毒性，这可能解释了为什么肿瘤细胞表现出耐受该化合物的尖锐阈值。在细胞培养物中，经 NBF-SPh 处理后，脂质过氧化作用增强（通过 2-硫代巴比妥酸反应物质测量），表明 ROS 显着积累。硫代甘油可以挽救细胞死亡并使存活率提高 15 倍至 20 倍，但丙酮酸和尿酸却是无效的保护剂。我们还观察到，每个 NBF-SPh 分子平均大约 19 个循环后，NBF-SPh 的氧化还原循环活性耗尽。电化学和计算分析表明，NBF-SPh 的部分还原增强了亲电性，这似乎促进了清除活性并导致亲电毒性。
Here, we report on 7-nitro-4-(phenylthio) benzofurazan (NBF-SPh), the most potent derivative among a set of patented anticancer 7-nitrobenzofurazans (NBFs), which have been suggested to function by perturbing protein–protein interactions. We demonstrate that NBF-SPh participates in toxic redox-cycling, rapidly generating reactive oxygen species (ROS) in the presence of molecular oxygen, and this is the first report to detail ROS production for any of the anticancer NBFs. Oxygraph studies showed that NBF-SPh consumes molecular oxygen at a substantial rate, rivaling even plumbagin, menadione, and juglone. Biochemical and enzymatic assays identified superoxide and hydrogen peroxide as products of its redox-cycling activity, and the rapid rate of ROS production appears to be sufficient to account for some of the toxicity of NBF-SPh (LC50 = 12.1 µM), possibly explaining why tumor cells exhibit a sharp threshold for tolerating the compound. In cell cultures, lipid peroxidation was enhanced after treatment with NBF-SPh, as measured by 2-thiobarbituric acid-reactive substances, indicating a significant accumulation of ROS. Thioglycerol rescued cell death and increased survival by 15-fold to 20-fold, but pyruvate and uric acid were ineffective protectants. We also observed that the redox-cycling activity of NBF-SPh became exhausted after an average of approximately 19 cycles per NBF-SPh molecule. Electrochemical and computational analyses suggest that partial reduction of NBF-SPh enhances electrophilicity, which appears to encourage scavenging activity and contribute to electrophilic toxicity.
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影响因子：
3.1
作者：
Baumann, RP;Seow, HA;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
11.2
作者：
Federici, Luca;Lo Sterzo, Carlo;Caccuri, Anna Maria
通讯作者：
Caccuri, Anna Maria
影响因子：
7.3
作者：
GHOSH, PB;WHITEHOUSE, MW;TERNAI, B
通讯作者：
TERNAI, B
影响因子：
4.1
作者：
GIULIVI, C;CADENAS, E
通讯作者：
CADENAS, E
影响因子：
7.4
作者：
Johnson, SAS;Dalton, AE;Pardini, RS
通讯作者：
Pardini, RS