IMPROVED HANDLES FOR SOLID PHASE PEPTIDE SYNTHESIS

固相肽合成的改进方法

• 批准号: 6342831
• 负责人: George Barany
• 金额: $ 24.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342831
• 关键词: chemical cleavage; chemical group; chemical stability; method development; peptide chemical synthesis; peptide library; polyethylene glycols

The solid-phase method introduced by Merrifield is now firmly established as a powerful technique for the study of bioligically important peptides, and indeed, it has been generalized to other biopolymers as well as many small organic compounds [combinatorial libraries]. Synthesis normally begins by covalently linking the starting (usually terminal) residue to an insoluble polymeric support. This anchoring step is an integral part of the overall synthetic plan, and the experimental details can impact significantly on the overall purity and yield of the final product. Handles are defined as bifunctional spacers, or linkers, which serve to achieve the required attachment in two discrete chemical steps. The handle approach allows precise control over the stability and ultimate cleavage of the anchoring linkage, and facilitates quantitative attachments which circumvent problems associated with extraneous polymer-bound functional groups. Under the aegis of the present research program, a number of handles [PAL, (R)PAL, HAL, XAL, BAL, NPE, Nonb, etc.] and polymeric supports [PEG-PS and CLEAR] have been developed and applied to the stepwise or segment condensation synthesis of challenging peptide targets. Some of these handle/support combinations are also appropriate for solid-phase organic synthesis. Compatible N alpha-amino [occasionally NW-amino] protection is provided principally by acid- labile tert-butyloxycarbonyl (Boc) or base-labile 9- fluorenylmethyloxycarbonyl (Fmoc) functions, and final cleavages occur under relatively mild conditions with minimal side reactions upon exposure to acid, base, light, fluoride ion, nucleophilic thiols, or palladium (0) in the presence of nucleophilic acceptors. Depending on the experimental design, the products can have a variety of endgroups (usually carboxylic acid or carboxamide), either completely free or else retaining side-chain protection. Some of the reagents and procedures developed in this research program have achieved widespread use throughout the world. The present competitive renewal application aims to expand on this progress and continue to demonstrate how the aforementioned handles can help address biologically significant challenges in synthetic peptide and combinatorial chemistry. Simultaneously, modified and new chemistries are being examined that may lead to new handles with even better properties and/or a wider range of uses. These methods will accommodate a range of scales, and be compatible with drug discovery programs and disease diagnosis procedures based on multiplex synthesis.

由梅里菲尔德介绍的固相法现在已被牢固地 作为一种强有力的技术，用于研究生物遗传学 重要的肽，事实上，它已被推广到其他 生物聚合物以及许多小的有机化合物[组合 图书馆]。 合成通常通过共价连接 起始（通常是末端）残基转移到不溶性聚合物载体上。 这个锚定步骤是整个合成计划的一个组成部分， 实验的细节会对整个 最终产物的纯度和产率。 句柄定义为 双功能间隔物或连接物，其用于实现所需的功能。 在两个独立的化学步骤中连接。 手柄方法允许 精确控制的稳定性和最终的分裂 锚定连接，并便于定量连接， 避免了与外来聚合物结合的官能化 组 在目前的研究计划的支持下， 手柄[PAL，（R）PAL，HAL，XAL，BAL，NPE，Nonb，etc.]和聚合物 支持[PEG-PS和CLEAR]已经开发并应用于 挑战性肽逐步或分段缩合合成 目标的 其中一些手柄/支架组合也是合适的 固相有机合成。 相容性N α-氨基 [偶尔NW-氨基]保护主要由酸提供， 不稳定的叔丁氧羰基（Boc）或碱不稳定的9- 芴基甲氧基羰基（Fmoc）功能，并发生最终裂解 在相对温和的条件下， 暴露于酸、碱、光、氟离子、亲核硫醇，或 钯（0）在亲核受体的存在下。 取决于 在实验设计中，产物可以具有多种端基 （通常是羧酸或羧酰胺），要么完全游离，要么 保留侧链保护。 一些试剂和程序 在这项研究计划中开发的，已经取得了广泛的使用 在全世界都有。 目前的竞争性续期申请旨在 扩大这一进展，并继续展示 上述手柄可以帮助解决生物学上显著的 在合成肽和组合化学的挑战。 与此同时，正在研究改进的和新的化学物质， 导致具有更好性能和/或更宽范围的 使用. 这些方法将适用于一系列尺度， 与药物发现计划和疾病诊断程序兼容 基于多路合成。

项目成果

On-resin native chemical ligation for cyclic peptide synthesis.

• DOI: 10.1021/jo049839d
• 发表时间: 2004-06
• 期刊: The Journal of organic chemistry
• 作者: Judit Tulla-Puche;G. Barany

Flexibility of interdomain contacts revealed by topological isomers of bivalent consolidated ligands to the dual Src homology domain SH(32) of abelson.

• DOI: 10.1021/bi982744j
• 发表时间: 1999-03
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Q. Xu;J. Zheng;R. Xu;G. Barany;D. Cowburn

Optimized preparation of deca(L-alanyl)-L-valinamide by 9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis on polyethylene glycol-polystyrene (PEG-PS) graft supports, with 1,8-diazobicyclo [5.4.0]-undec-7-ene (DBU) deprotection.

• 发表时间: 1996-05
• 期刊: Peptide research
• 作者: S. Kates;N. Solé;M. Beyermann;G. Barany;F. Albericio

Unexpectedly Stable (Chlorocarbonyl)(N-ethoxycarbonylcarbamoyl)disulfane, and Related Compounds That Model the Zumach-Weiss-Kühle (ZWK) Reaction for Synthesis of 1,2,4-Dithiazolidine-3,5-diones.

出乎意料地稳定的（氯羰基）（N-乙氧基羰基氨基甲酰基）二硫烷以及模拟 Zumach-Weiss-Kühle (ZWK) 反应以合成 1,2,4-二噻唑烷-3,5-二酮的相关化合物。

• DOI: 10.1021/acs.joc.5b01826
• 发表时间: 2015
• 期刊: The Journal of organic chemistry
• 作者: Barany,George;Britton,Doyle;Chen,Lin;Hammer,RobertP;Henley,MadeleineJ;Schrader,AlexM;YoungJr,VictorG
• 通讯作者: YoungJr,VictorG

Acidolytic cleavage of tris(alkoxy)benzylamide (PAL) "internal reference" amino acyl (IRAA) anchoring linkages: validation of accepted procedures in solid-phase peptide synthesis (SPPS).

三（烷氧基）苯甲酰胺（PAL）“内参”氨基酰基（IRAA）锚定键的酸解裂解：固相肽合成（SPPS）中公认程序的验证。

• DOI: 10.1111/j.1399-3011.1993.tb00339.x
• 发表时间: 1993
• 期刊: International journal of peptide and protein research
• 作者: Albericio,F;Barany,G
• 通讯作者: Barany,G