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. 本研究的重点是开发构建 C-N 的有效方法 生物活性天然产物和肽结构（例如糖蛋白）中的键。那里 由于杂环和肽结构的普遍存在，对它们的有效合成提出了巨大的需求 作为制药先导目标。指导的 K99 阶段研究将重点开发 获得有角度取代的十氢喹啉的方法。此方法将能够快速访问 最近分离出的乙酰胆碱酯酶抑制剂lycojapodine A。独立的R00期研究将在 集中于使用以氮为中心的自由基的新反应方法。一、努力方向 一种形成在环连接处含有叔胺的多环结构的方法。这 该方法将用于生物碱亮氨酸家族的合成，该生物碱可逆转长春新碱 KB细胞的抵抗力。此外，解决肽连接这一长期挑战的新方法将是 追击。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，并将简化均质糖蛋白的合成。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，并 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。