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.

我们的第一个特异性目标进一步发展了膜活性抗生素序列的概念