Innovative Medicinal Chemistry

我们的第一个具体目标是进一步发展膜活性抗生素序列的概念 葛兰米菌素S(GS)可用于将生物活性有效载荷运送到线粒体。具体地说，我们将构建比4-氨基-TEMPO连接的JP4-039和XJB-5-131具有更高催化活性的杂化分子。 第二个特定目的是提供与一氧化氮合酶抑制剂相关的分子，如AMT(GS-NOS-I)，这将检验项目1的假设，即线粒体靶向的小一氧化氮合酶抑制剂将单独有效，当添加到GS-氮氧化物中时，作为辐射损伤缓释剂。第三个特定目标验证了这样一种假设，即通过GS-氮氧化物和GS-NOS-1以及其他组合疗法的纳米颗粒结合，可以实现辐射缓解中的相加和协同效应。第四个具体目标将支持项目4，并提供原理证明，即过氧化氢(H202)释放的小分子可以诱导具有完整活性的人(Rh)MnSOD形成高分子量低聚物。H202对MnSOD活性的影响可能是由于寡聚诱导的酶结构的稳定。因此，它可以作为一种保护策略来补充辐射所致的MnSOD缺乏症。第五个具体目标是合成三苯基膦(TPP)衍生的肟、氮氧化物、Salen-Mn和卟啉-Mn络合物，从而采用电荷驱动的放射防护剂向线粒体递送的策略。第六个具体目标是合成项目先导结构的一般类似物，发展所有候选药物和先导化合物的结构-活性关系，以及匹兹堡CMCR的任何项目和非合成核心中任何其他合成化合物的克级放大。具体地说，核心D将与项目5合作优化PUMA抑制剂，并与核心C和E合作优化给药系统。

Our First Specific Aim further develops the concept that sequences of the membrane-active antibiotic Gramicidin S (GS) can be used to deliver biologically active payloads to mitochondria. Specifically, we will construct hybrid molecules with higher catalytic activity than 4-amino-Tempo linked JP4-039 and XJB-5-131. The Second Specific Aim provides molecules linked to NOS inhibitors such as AMT (GS-NOS-I), which will test the hypothesis of Project 1 that mitochondrial targeted small NOS inhibitors will be effective alone and when added to GS-nitroxides as radiation damage mitigators. The Third Specific Aim tests the hypothesis that additive and synergistic effects in radiation mitigation can be accomplished by nanoparticle conjugation of GS-nitroxide and GS-NOS-1 as well as other combination therapeutics. The Fourth Specific Aim will support Project 4 and provide proof-of-principle that hydrogen peroxide (H202) releasing small molecules can induce the formation of high molecular weight oligomers of human (rh)MnSOD with intact activity. This effect of H202 on MnSOD activity is likely due to the oligomerization-induced stabilization of the enzyme's structure. Therefore, it can be used as a protective strategy to replenish irradiation induced MnSOD deficiency. The Fifth Specific Aim is directed toward the synthesis of triphenylphosphonium (TPP)-derived oximes, nitroxides, salen-Mn and porphyrin-Mn complexes and thus employs a charge-driven delivery strategy of radioprotective agents to mitochondria. The Sixth Specific Aim is focused on the synthesis of general analogs of Project lead structures, the development of structure-activity relationships of all drug and lead candidates, and the gram-level scaleup of any other synthetic compounds in any ofthe Projects and non-synthetic Cores ofthe Pittsburgh CMCR. Specifically, Core D will optimize PUMA inhibitors in collaboration with Project 5, and optimize delivery systems in collaboration with Cores C and E.