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这样的概念，即膜活性抗生素的序列 短杆菌肽S（GS）可用于将生物活性有效载荷递送至线粒体。具体地，我们将构建具有比4-氨基-Tempo连接的JP 4 -039和XJB-5-131更高的催化活性的杂合分子。 第二个具体目标提供了与NOS抑制剂如AMT（GS-NOS-I）相关的分子，这将测试项目1的假设，即线粒体靶向的小NOS抑制剂单独有效，以及当添加到GS-氮氧化物中作为辐射损伤缓解剂时有效。第三个具体目标测试了这样的假设，即辐射缓解中的加和和协同效应可以通过GS-氮氧化物和GS-NOS-1的纳米颗粒缀合以及其他组合治疗剂来实现。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（H2 O2）释放小分子可诱导形成具有完整活性的人（rh）MnSOD的高分子量寡聚体。H2 O2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。因此，它可以作为补充辐射引起的MnSOD缺陷的保护策略。第五个具体目标是针对合成三苯基鳞（TPP）衍生的肟、氮氧化物、salen-Mn和卟啉-Mn络合物，并因此采用电荷驱动的放射防护剂向线粒体的递送策略。第六个具体目标的重点是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-活性关系的发展，以及匹兹堡CMCR的任何项目和非合成核心中的任何其他合成化合物的克级放大。具体而言，核心D将与项目5合作优化BRA抑制剂，并与核心C和E合作优化递送系统。