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(申请人提供)：拟议研究的重点是开发在具有生物活性的天然产物和多肽结构(如糖蛋白)的背景下构建C-N键的有效方法。由于杂环和多肽结构作为药物先导靶标的广泛应用，人们对它们的有效合成有很大的需求。指导的K99阶段研究将集中于开发一种方法学来获得角度取代的十氢喹啉类药物。这种方法将使人们能够快速获得最近分离的乙酰胆碱酯酶抑制剂赖氨酸A。独立的R00阶段的研究将集中在使用以氮为中心的自由基进行新的反应方法。首先，将致力于一种在环连接处形成含有叔胺的多环结构的方法。这种方法将用于合成亮氨酸生物碱家族，逆转KB细胞对长春新碱的耐药性。此外，将寻求一种新的方法来应对多肽连接这一长期存在的挑战。总之，建议的方法将使人们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靶点和糖蛋白同质版本的机会，这将使研究它们在细胞过程和疾病中的功能成为可能。 公共卫生相关性：斯托克迪尔，詹妮弗L.拟议的研究与公共健康相关，因为它将使人们能够快速获得融合和桥联的多环叔胺产品，从而加快生物活性小分子的合成。此外，它将允许无差向异构化的多肽连接，大大简化了合成均一糖蛋白的方法。这些项目得到了NIH使命的支持，该使命旨在促进基本的创造性发现，旨在提高国家治疗人类疾病的能力。