GS-氮氧化物类似物JP4-039作为全身照射减轻剂的有效性。
Effectiveness of Analogs of the GS-Nitroxide, JP4-039, as Total Body Irradiation Mitigators.
作者信息
Epperly Michael W, Sacher Joshua R, Krainz Tanja, Zhang Xiaolin, Wipf Peter, Liang Mary, Fisher Renee, Li Song, Wang Hong, Greenberger Joel S
机构信息
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, U.S.A.
出版信息
In Vivo. 2017 Jan 2;31(1):39-43. doi: 10.21873/invivo.11022.
Abstract
BACKGROUND/AIM: Mitochondrial-targeted gramicidin S (GS)-nitroxide, JP4-039, has been demonstrated to be a potent radiation mitigator, and safe over a wide dose range. In addition, JP4-039 has organ-specific effectiveness when locally applied.
MATERIALS AND METHODS
We tested the effect of another GS-nitroxide, XJB-5-131, which has more effective mitochondrial localization, and compared these results to those for radiation mitigation against the hematopoietic syndrome, and two analogs of JP4-039, which have the same mitochondrial localization signal, but different chemical payloads: JRS527.084 contains a second nitroxide per molecule, and TK649.030 contains an ester group attached to the nitroxide.
RESULTS
The results demonstrate the superiority of JP4-039 as a systemic radiation mitigator.
CONCLUSION
Structure-activity relationships and bioassays demonstrate that JP4-039 is an optimized small-molecule radiation mitigator.
摘要
背景/目的：线粒体靶向短杆菌肽S（GS）-氮氧化物JP4-039已被证明是一种有效的辐射缓解剂，且在很宽的剂量范围内都安全。此外，JP4-039局部应用时具有器官特异性疗效。
材料与方法
我们测试了另一种GS-氮氧化物XJB-5-131的效果，其具有更有效的线粒体定位，并将这些结果与针对造血综合征的辐射缓解效果进行比较，还测试了JP4-039的两种类似物，它们具有相同的线粒体定位信号，但化学负载不同：JRS527.084每个分子含有第二个氮氧化物，TK649.030含有连接到氮氧化物上的酯基。
结果
结果证明了JP4-039作为全身辐射缓解剂的优越性。
结论
构效关系和生物测定表明JP4-039是一种优化的小分子辐射缓解剂。
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J Invest Dermatol. 2017 Mar;137(3):576-586. doi: 10.1016/j.jid.2016.09.033. Epub 2016 Oct 26.
2
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ACS Cent Sci. 2016 Sep 28;2(9):653-659. doi: 10.1021/acscentsci.6b00199. Epub 2016 Sep 7.
3
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Radiat Res. 2016 Feb;185(2):134-50. doi: 10.1667/RR14035.1. Epub 2016 Jan 20.
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8
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Mol Pharm. 2013 Jan 7;10(1):187-98. doi: 10.1021/mp300319m. Epub 2012 Dec 17.
9
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10
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