Novel Techniques for the Synthesis and Coupling of Peptide Segments

肽片段合成和偶联的新技术

• 批准号: 9003192
• 负责人: Louis Carpino
• 金额: $ 21.55万
• 依托单位: University of Massachusetts Amherst
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9003192&HistoricalAwards=false
• 关键词: Novel; Techniques; Synthesis; Coupling; Peptide

This research is being funded by the Organic Synthesis Chemistry Program. New techniques for the synthesis of naturally occurring medium or long chain peptides are being developed which will make them rapidly available in multi-gram quantities for testing purposes. New synthetic techniques based on base- and solvent-sensitive amino-protecting groups promise to make available quickly multi-gram quantities of shorter peptides and to markedly improve the synthesis of small quantities of longer peptides. Methods for the synthesis of long peptide chains of 100 or more amino acid units which involve the coupling of segments enjoy significant advantages over those involving stepwise approaches. Three methods for assembling the appropriate segments will be studied: (a) the FMOC/Polyamine solution technique, (b) the two polymer ("inverse merrifield") approach and (c) the standard Merrifield solid phase method. In all three approaches the applicability of newly-discovered FMOC amino acid fluorides as rapid-acting, inexpensive coupling agents will be studied. Such reagents are now available for all but four of the common amino acids. Synthesis of appropriate acid fluoride reagents for these four compounds (Arg, Asn, Gln, His) will be developed. To facilitate solid phase syntheses two special resin supports will be investigated: (a) tertiary alcohol resins which should completely inhibit loss of peptide from the resin due to diketopiperazine formation at the depeptide stage, especially in the case of C-terminal or penultimate proline or glycine and (b) resin supports bearing tertiary aminoalcohol functions which should serve to catalyse loading of the first amino acid and thereby promote complete on-line automated syntheses from the first to the last amino acid. Once rapid, routine methods for the synthesis of protected segments are available, both solution and solid phase methods of segment coupling will be examined. A novel method of effecting racemization-free segment coupling involving protection of the C-terminal amide bond by FM-bar or a related amide protectant will be pursued. The model chosen to study the application of these techniques is a 19-unit segment of a silkworm prothoracicotropic hormone, PTTH-II-(1-19).

这项研究由有机合成化学计划资助。 合成天然存在的中链或长链肽的新技术正在开发中，这将使它们能够快速以数克的量用于测试目的。 基于对碱和溶剂敏感的氨基保护基团的新合成技术有望快速提供数克数量的较短肽，并显着改善少量较长肽的合成。 涉及片段偶联的100个或更多氨基酸单元的长肽链的合成方法比涉及逐步方法的方法具有显着的优势。 将研究三种组装适当片段的方法：（a）FMOC/聚胺溶液技术，（b）两种聚合物（“逆梅里菲尔德”）方法和（c）标准梅里菲尔德固相方法。 在这三种方法中，我们将研究新发现的 FMOC 氨基酸氟化物作为快速作用、廉价偶联剂的适用性。 这些试剂现在可用于除四种常见氨基酸之外的所有氨基酸。 将开发适合这四种化合物（Arg、Asn、Gln、His）的酰基氟试剂的合成。 为了促进固相合成，将研究两种特殊的树脂支持物：（a）叔醇树脂，其应完全抑制由于在肽阶段形成二酮哌嗪而导致的肽从树脂中损失，特别是在C末端或倒数第二个脯氨酸或甘氨酸的情况下；（b）具有叔氨基醇功能的树脂支持物，其应用于催化第一个氨基的负载 酸，从而促进从第一个氨基酸到最后一个氨基酸的完整在线自动化合成。 一旦可用于合成受保护片段的快速、常规方法可用，片段偶联的溶液和固相方法将被检查。 将寻求一种实现无外消旋链段偶联的新方法，涉及通过 FM-bar 或相关酰胺保护剂保护 C 末端酰胺键。 选择研究这些技术应用的模型是蚕促胸腺激素 PTTH-II-(1-19) 的 19 个单位片段。