SYNTHESIS OF ANTIBIOTICS

抗生素的合成

• 批准号: 7388145
• 负责人: K. C. NICOLAOU
• 金额: $ 57.29万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388145
• 关键词: Alkenes; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Arts; Biological; Biological Factors; Class; Development; Disease; Drug Design; Evaluation; Funding; Knowledge; Lead; Methodology; Molecular; Molecular Structure; Palladium; Purpose; Reaction; Research; Research Activity; Technology; Testing; Thiostrepton; Work; analog; antibiotic design; chemical synthesis; complement C4c; complement C4d; design; design and construction; hydroxyindole; member; nocathiacin I; programs

The competitive renewal proposal describes a research program directed at the total synthesis of naturally occurring antibiotics and designed antibacterial agents. The proposed work represents continuation of our NIH-funded (AI55475) research activities and will specifically involve molecular design and synthetic work toward thiostrepton (1), nocathiacin I (2), marinomycin A (3) and abyssomycin C (4c) and their analogs. In the thiostrepton project, we plan to optimize a biologically active lead compound representing the didehydropiperidine domain of the molecule that we have discovered during our successful total synthesis of this antibiotic. In the nocathiacin I project we will follow our recently developed methodology for W-hydroxyindole synthesis to achieve a total synthesis of the natural product and apply the technology to the construction of designed analogs for the purposes of SAR studies. The total synthesis of marinomycin A is designed to test the scope and limitations of the palladium-catalyzed cross-coupling and olefin metathesis reactions. The designed total synthesis of abysommycin C relies on a biosynthetic hypothesis cascade and is expected to deliver other members of the class, including designed analogs for biological evaluation. Overall, this research program aims to generate new knowledge for the treatment of anti- infective diseases, advance the art of chemical synthesis as applied to drug design and development, and, possibly, result in the synthesis of new potential antibacterial agents.

竞争性更新提案描述了一项针对总 天然抗生素和设计的抗菌剂的合成。的 拟议的工作代表了我们NIH资助（AI 55475）研究活动的继续 并将具体涉及硫链丝菌素的分子设计和合成工作 (1)、诺卡霉素I（2）、海霉素A（3）和阿比索霉素C（4c）及其类似物。在 在硫链丝菌素项目中，我们计划优化一种具有生物活性的先导化合物 代表我们发现的分子的二脱氢哌啶结构域 在我们成功地全合成这种抗生素的过程中。在Nocathiacin I项目中， 将遵循我们最近开发的W-羟基吲哚合成方法， 实现天然产物的全合成，并将该技术应用于 构建用于SAR研究目的的设计类似物。的全合成 Marinomycin A旨在测试钯催化的 交叉偶联和烯烃复分解反应。设计的全合成 深海霉素C依赖于生物合成假设级联，预计将提供 该类的其他成员，包括用于生物学评价的设计类似物。 总的来说，这项研究计划的目的是产生新的知识，治疗抗- 感染性疾病，推进应用于药物设计的化学合成艺术， 开发，并可能导致新的潜在抗菌剂的合成。