Core--Medicinal chemistry: discovery and screening

活性氧（ROS）和线粒体的清除剂！一氧化氮合酶（mtNOS）抑制剂在新型口服放射防护剂和缓解剂的开发中起关键作用。核心部分有两个相互依存的综合部分：（a）药物（发现）化学和（B）药理学评价和制剂。核心的药物（发现）化学部分的总体目标是提供新的，化学可逆的，因此定时释放的药物。核心药理学部分的总体目标是提供资源，以允许体外高通量筛选化学文库，提供新合成化合物的细胞活性的初步评价，并为CMCR项目和核心进行制剂和稳定性研究。我们有五项具体任务： 1.制备基于肽模拟物的ROS清除剂的定时释放衍生物（克里思 衍生物）和mtNOS抑制剂。这些试剂将是细胞可渗透的和膜靶向的。 2.合成细胞渗透性肽抗氧化剂，专门针对线粒体内膜。 3.实施自动化高通量筛选分析。 4.在完整细胞中对新合成的化合物进行多参数分析。 5.配制用于体内静脉内和口服使用的化合物，评估化学提取方法以制备用于分析的样品，并确定化合物在水性和生物液体中的稳定性。

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.