Scavengers of reactive oxygen species (ROS) and mitochondria! nitric oxide synthase (mtNOS) inhibitors play a key role in the development of novel orally administrable radioprotectants and mitigators. The Core has two interdependent and integrated Sections: (a) Medicinal (Discovery) Chemistry, and (b) Pharmacological Evaluation and Formulation. The overall goal of the Medicinal (Discovery) Chemistry section of the Core is to provide novel, chemoreversible and thus timed-release agents. The overall goal of the Pharmacology Section of the Core is to provide resources to allow in vitro high throughput screening of chemical libraries, to provide an initial evaluation of the cellular activity of newly synthesized compounds, and to conduct formulation and stability studies for the CMCR Projects and Cores. We have five specific tasks: 1. Preparation of peptide mimetics based timed-release derivatives of ROS scavengers (TEMPO derivatives) and mtNOS inhibitors. These agents will be cell-permeable and membrane-targeted. 2. Synthesis of cell-permeable peptide antioxidants specifically targeted to the inner mitochondrial membrane. 3. Implementing automated high throughput screening assays. 4. Conducting multiparametric analyses of newly synthesized compounds in intact cells. 5. Formulating compounds for in vivo intravenous and oral use, evaluating chemical extraction methods to prepare the samples for analytical analysis, and determine compound stability in aqueous and biological fluids.
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