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

描述（由申请人提供）：拟议研究的重点是在生物活性天然产物和肽结构（如糖蛋白）的背景下开发构建C-N键的有效方法。由于杂环和肽结构作为药物先导靶点的普遍存在，因此对高效合成它们的需求很大。指导的K99阶段研究将侧重于开发一种获取角取代十氢喹啉的方法。该方法将能够快速获得最近分离的乙酰胆碱酯酶抑制剂lycojapodine A.独立的R00相研究将集中在利用氮中心自由基进行新的反应方法。首先，努力将指向一种在环结处含有叔胺的多环结构的形成方法。该方法将用于合成能逆转KB细胞长春新碱耐药的白垩碱家族生物碱。此外，一种新的方法来长期挑战肽连接将被追求。总之，所提出的方法将能够更有效地获得天然产物中普遍存在的具有挑战性的结构，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靶点和糖蛋白的同质版本，这将使研究其在细胞过程和疾病中的功能成为可能。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Stockdill, Jennifer L. The proposed research is relevant to public health because it will enable rapid access to fused and bridged polycyclic tertiary amine products, thereby expediting the synthesis of bioactive small molecules. Furthermore, it will allow for an epimerization-free peptide ligation, substantially simplifying the synthetic approach toward homogeneous glycoproteins. These projects are supported by the NIH's mission to foster fundamental creative discoveries directed toward improving the Nation's ability to cure human diseases.