Studies in Amide and Peptide Synthesis

酰胺和肽合成研究

• 批准号: 8829285
• 负责人: Jeffrey Nicholas Johnston
• 金额: $ 32.78万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829285
• 关键词: Address; Adopted; Amides; Amines; Amino Acids; Attention; Benchmarking; Biologic Development; Biological Factors; Biophysics; Carbon; Carboxylic Acids; Chemicals; Complement; Coupling; Cyclic Peptides; Development; Esters; Excision; Expeditions; Goals; Halogens; Health; Human; In Situ; Ions; Laboratories; Life; Methods; Molecular Weight; Names; Nature; Nitrogen; Nylons; Organic Chemistry; Peptide Synthesis; Peptides; Pharmaceutical Chemistry; Pharmacologic Substance; Preparation; Process; Reaction; Reaction Time; Reagent; Relative (related person); Reporting; Scheme; Site; Source; Speed; Stereoisomer; Techniques; Technology; Therapeutic; Therapeutic Uses; Water; Work; aqueous; base; carbanion; chemical synthesis; cost; epimerization; glycine amide; improved; innovation; interest; nitroalkane; novel; novel strategies; peptide chemical synthesis; programs; small molecule; structural biology; success; tool

DESCRIPTION (provided by applicant): This proposal seeks support to develop a fundamentally new approach to amide and peptide chemical synthesis, one that complements existing methods based on dehydrative amide synthesis using carboxylic acids and amines. Bromonitroalkanes serve as carboxylic acid surrogates in a direct amide synthesis that utilizes an amine acceptor and an activating agent (a halonium ion). The concise preparation of amides derived from nonnatural amino acids, common constituents of biologically active linear and cyclic peptides that have been isolated from natural sources, is a central theme. Without this new paradigm, alternative chemical methods would provide access to the desired amides at the cost of a large number of steps, and the contamination of intermediates and products by stereoisomers that are difficult to remove. The practical chemical synthesis of biologically active peptides is an immediate goal. In the short term, peptides of modest size (~10 residues) will be prepared and diversified using the principles of medicinal chemistry. In the long term, use of this novel amide synthesis will be used in combination with conventional methods to provide access to large peptides (e.g. biologics) modified site-specifically with nonnatural amino acids.

描述（由申请人提供）：该提案寻求支持以开发一种从根本上进行酰胺和肽化学合成的方法，该方法使用羧酸和胺对基于脱水酰胺合成的现有方法进行了补充。 Bromonitroalkanes在使用胺受体和激活剂（Halonium Ion）的直接酰胺合成中充当羧酸替代物。源自非天然氨基酸的酰胺的简洁制备，这是从天然来源分离的生物活性线性和环状肽的共同成分，是一个中心主题。如果没有这种新的范式，替代化学方法将以大量步骤的代价为所需的酰胺提供访问，并且被立体异构体对中间体和产品的污染很难去除。生物活性的实际化学合成 肽是一个直接目标。在短期内，将使用药物化学原理制备和多样化的适度大小（约10个残基）的肽。从长远来看，使用此 新型酰胺合成将与常规方法结合使用，以提供与非天然氨基酸特定于修饰的大型肽（例如生物制剂）的访问。