SYNTHESIS OF ANTIBIOTICS

抗生素的合成

• 批准号: 7030614
• 负责人: K. C. NICOLAOU
• 金额: $ 55.77万
• 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/7030614
• 关键词: aminoglycoside antibiotics; cyclization; drug design /synthesis /production; heterocyclic polycyclic compound

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：竞争性更新提案描述了一项针对天然抗生素和设计抗菌剂全合成的研究计划。拟议的工作代表了我们NIH资助的（AI 55475）研究活动的继续，并将具体涉及硫链丝菌素（1），诺卡氏素I（2），marinomycin A（3）和abyssomycin C（4c）及其类似物的分子设计和合成工作。在thiostrepton项目中，我们计划优化一种具有生物活性的先导化合物，该化合物代表了我们在成功合成这种抗生素期间发现的分子的二脱氢哌啶结构域。在Nocathiacin I项目中，我们将遵循我们最近开发的W-羟基吲哚合成方法，以实现天然产物的全合成，并将该技术应用于SAR研究目的的设计类似物的构建。海霉素A的全合成旨在测试钯催化的交叉偶联和烯烃复分解反应的范围和局限性。设计的深海霉素C的全合成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。总体而言，该研究计划旨在产生用于治疗抗感染疾病的新知识，推进应用于药物设计和开发的化学合成技术，并可能导致新的潜在抗菌剂的合成。