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）：该提案寻求支持开发一种全新的酰胺和肽化学合成方法，该方法补充了基于使用羧酸和胺的脱水酰胺合成的现有方法。溴硝基烷烃在利用胺受体和活化剂（卤离子）的直接酰胺合成中用作羧酸替代物。从非天然氨基酸（从天然来源中分离出来的具有生物活性的线性和环肽的常见成分）衍生的酰胺的简洁制备是一个中心主题。如果没有这种新范例，替代化学方法将需要大量步骤才能获得所需的酰胺，并且中间体和产物会受到难以去除的立体异构体的污染。生物活性物质的实用化学合成 肽是当前的目标。短期内，将利用药物化学原理制备适度大小的肽（~10 个残基）并使其多样化。从长远来看，使用这个 新型酰胺合成将与传统方法结合使用，以提供用非天然氨基酸进行位点特异性修饰的大肽（例如生物制剂）。