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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

基本信息

批准号：
8721435
负责人：
Jennifer Lynn Stockdill
金额：
$ 30.42万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-08-31
项目状态：
已结题

项目摘要

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·斯托克迪尔，Jennifer L. 提出的研究重点是开发高效的C-N构建方法在生物活性天然产物和多肽结构的背景下的键，例如糖蛋白。那里由于杂环和多肽结构的流行，对有效合成它们的需求很大作为药物的先导靶子。指导K99阶段的研究将集中在开发一种获取角度取代的十氢喹啉类药物的方法学。此方法将允许快速访问最近分离的乙酰胆碱酯酶抑制剂赖氨酸A将进行独立的R00期研究以氮为中心的自由基的使用为新的反应方法。一是着力抓好涉及一种在环交界处形成含有叔胺的多环结构的方法。这方法将用于合成逆转长春新碱的亮氨酸生物碱家族 KB细胞中的抗性。此外，一种新的方法将解决长期存在的多肽连接的挑战被追捕。总之，建议的方法将使您能够更高效地访问具有挑战性的体系结构在天然产品中普遍存在，并将简化均一糖蛋白的合成。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糖蛋白的同质版本，这将使研究它们在细胞过程中的功能和疾病。