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: 8091059
• 负责人: Jennifer Lynn Stockdill
• 金额: $ 9万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091059
• 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

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.

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（例如糖蛋白）的背景下开发有效的C-N键方法。由于其流行率是药物铅靶标，因此对杂环和肽结构有效合成的需求很大。受过指导的K99阶段研究将着重于开发一种方法，以访问角度取代的Decahydroquinolines。该方法将使最近分离的乙酰胆碱酯酶抑制剂Lycojapodine A快速进入A.独立的R00相研究将集中于使用以氮为中心的自由基用于新的反应方法。首先，努力将针对一种在环连接处形成含三胺的多环状结构的方法。该方法将用于生物碱的白细胞素家族的合成，后者在KB细胞中逆转vincristine的耐药性。此外，将采取一种新的应对肽结扎挑战的新方法。共同提出的方法将使在天然产品中普遍存在的具有挑战性的体系结构，并将简化均质糖蛋白的合成。因此，拟议的研究将改善获得重要的铅靶标，以治疗疾病和均质糖蛋白的均质版本，这将使它们在细胞过程和疾病中的功能进行研究。 公共卫生相关性：Stockdill，Jennifer L.拟议的研究与公共卫生有关，因为它将能够快速进入融合和桥接的多环胺产品，从而加快生物活性小分子的合成。此外，它将允许进行无染色的肽连接，从而实质上简化了均质糖蛋白的合成方法。 NIH的使命支持这些项目，旨在培养旨在提高国家治愈人类疾病能力的基本创造性发现。