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: 8545182
• 负责人: Jennifer Lynn Stockdill
• 金额: $ 23.71万
• 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/8545182
• 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.

项目总结/摘要Stockdill，Jennifer L. 建议研究的重点是发展有效的方法来构建C-N 在生物活性天然产物和肽结构如糖蛋白的背景下，那里 由于杂环和肽结构的普遍存在， 作为制药业的主要目标K99阶段的研究将侧重于开发一种 获得角取代的十氢喹啉的方法。这种方法将使快速访问 最近分离的乙酰胆碱酯酶抑制剂lycojapodine A。独立的R 00阶段研究将 以氮为中心的自由基用于新的反应方法为中心。一是定向发力 涉及在环连接处含有叔胺的多环结构的形成方法。这 方法将被用于合成明康碱家族的生物碱，其逆转长春新碱 KB细胞中的抗性。此外，一种新的方法，长期的挑战肽连接将是 追求。总之，所提出的方法将能够更有效地访问具有挑战性的架构， 在天然产物中普遍存在，并将使同质糖蛋白的合成流线化。因此 拟议的研究将改善获得治疗疾病的重要先导目标的机会， 糖蛋白的同质版本，这将使研究它们在细胞过程中的功能成为可能， 疾病