C-N Bond-Forming Methodologies for the Synthesis of Small Molecules and Peptides

用于合成小分子和肽的 C-N 键形成方法

• 批准号: 8534978
• 负责人: Jennifer Lynn Stockdill
• 金额: $ 24.9万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534978
• 关键词: Acetylcholinesterase Inhibitors; Alder plant; Alkaloids; Amides; Amino Acids; Architecture; Biological Factors; Biological Process; Biomedical Research; Cell physiology; Chemistry; Cyclization; Development; Diels Alder reaction; Disease; Electronics; Family; Fostering; Glycoproteins; Goals; HIV; Improve Access; KB Cells; Lead; Ligation; Literature; Medical; Mentors; Methodology; Methods; Mission; Multi-Drug Resistance; Nitrogen; Outcome; Peptides; Pharmacologic Substance; Phase; Positioning Attribute; Prevalence; Property; Public Health; Reaction; Research; Resistance; Role; Scheme; Structure; System; Testing; Therapeutic; Vincristine; alkyl group; base; cycloaddition; design; diene; epimerization; experience; human disease; improved; novel; novel strategies; prevent; programs; skills; small molecule; tertiary amine; thioester

PROJECT SUMMARY/ABSTRACT Stockdill, Jennifer L. The focus of the proposed research is the development of efficient methods for the construction of C-N bonds in the context of biologically active natural products and peptidic structures such as glycoproteins. There is significant demand for efficient syntheses of heterocyclic and peptidic structures because of their prevalence as pharmaceutical lead targets. The mentored K99 phase research will focus on the development of a methodology to access angularly-substituted decahydroquinolines. This method will enable rapid access to the recently isolated acetylcholinesterase inhibitor lycojapodine A. The independent R00 phase research will be centered on the use of nitrogen-centered radicals for new reaction methods. First, efforts will be directed toward a method for the formation of polycyclic structures containing a tertiary amine at a ring junction. This method will be utilized in the synthesis of the leuconicine family of alkaloids, which reverse vincristine resistance in KB cells. Additionally, a novel approach to the long-standing challenge of peptide ligation will be pursued. Together, the proposed methods will enable more efficient access to challenging architectures that are prevalent in natural products and will streamline the synthesis of homogeneous glycoproteins. Thus, the proposed research will improve access to important lead targets for the treatment of illnesses and to homogeneous versions of glycoproteins, which will enable studies of their function in cellular processes and diseases.

项目摘要/摘要Stockdill，Jennifer L. 拟议研究的重点是开发C-N的有效方法 在生物活性天然产物和肽结构（例如糖蛋白）的背景下的键。那里 是对杂环和肽结构有效合成的重大需求 作为药物铅靶标。指导的K99阶段研究将重点放在 访问角度取代的Decahydroquinolines的方法。此方法将使快速访问 最近分离的乙酰胆碱酯酶抑制剂Lycojapodine A.独立的R00相研究将是 集中于使用以氮为中心的自由基用于新的反应方法。首先，努力将被指导 迈向一种在环连接处形成含三胺的多环状结构的方法。这 方法将用于生物碱的白细胞素家族的合成，该家族会反向vincristine逆转 KB细胞的抗性。此外，应对肽连接长期挑战的新方法将是 追捕。提出的方法一起将使更有效地访问具有挑战性的体系结构 在天然产物中很普遍，并将简化均质糖蛋白的合成。因此， 拟议的研究将改善对疾病治疗的重要铅目标的机会 糖蛋白的均质版本，这将使它们在细胞过程中的功能和 疾病。