Innovative Medicinal Chemistry

创新药物化学

• 批准号: 8010806
• 负责人: Peter Wipf
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010806
• 关键词: Alkenes; Amides; Antibiotics; Biological; Cells; Charge; Collaborations; Complex; Development; Evaluation; Generations; Gramicidin; Grant; Human; Hybrids; Hydrogen Peroxide; Lead; Link; Membrane; Methodology; Mitochondria; Modification; Molecular Weight; Mus; Organelles; Oxidation-Reduction; Oximes; Pathology; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Porphyrins; Process; Radiation; Radiation Protection; Radiation therapy; Radiation-Protective Agents; Reactive Oxygen Species; Relative (related person); Resources; Role; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; analog; base; cell injury; enzyme structure; inhibitor/antagonist; innovation; irradiation; nanoparticle; next generation; novel; salen; scale up; small molecule; tool; zirconocene

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.

我们的第一个具体目标进一步发展了膜活性抗生素序列的概念 短杆菌肽 S (GS) 可用于将生物活性有效负载递送至线粒体。具体来说，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。 第二个具体目标提供与 AMT (GS-NOS-I) 等 NOS 抑制剂相关的分子，这将检验项目 1 的假设，即线粒体靶向的小 NOS 抑制剂单独使用以及添加到 GS-硝基氧作为辐射损伤缓解剂时均有效。第三个具体目标测试了以下假设：通过 GS-硝基氧和 GS-NOS-1 的纳米粒子缀合以及其他组合疗法可以实现辐射缓解中的累加和协同效应。第四个具体目标将支持项目 4 并提供原理证明，即释放小分子的过氧化氢 (H2O2) 可以诱导具有完整活性的人 (rh)MnSOD 高分子量低聚物的形成。 H 2 O 2 对MnSOD活性的这种影响可能是由于寡聚化诱导的酶结构的稳定化所致。因此，它可以作为补充辐射引起的 MnSOD 缺乏的保护策略。第五个具体目标是合成三苯基鏻 (TPP) 衍生的肟、硝基氧、salen-Mn 和卟啉-Mn 复合物，从而采用电荷驱动的辐射防护剂递送策略至线粒体。第六个具体目标侧重于项目先导结构的一般类似物的合成，所有药物和先导候选物的结构-活性关系的开发，以及匹兹堡 CMCR 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。具体来说，Core D将与Project 5合作优化PUMA抑制剂，并与Cores C和E合作优化递送系统。