Michael W Epperly1, Joshua R Sacher2,3, Tanja Krainz2,3, Xiaolin Zhang2,3, Peter Wipf2,3, Mary Liang2,3, Renee Fisher1, Song Li4, Hong Wang1, Joel S Greenberger5. 1. Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A. 2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, U.S.A. 3. Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA, U.S.A. 4. School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, U.S.A. 5. Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A. greenbergerjs@upmc.edu.
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. Copyright
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. Copyright
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