IMPROVED HANDLES FOR SOLID PHASE PEPTIDE SYNTHESIS

由Merrifield提出的固相法现在是坚定的 作为生物组学研究的一种强有力的技术 重要的多肽，事实上，它已经被推广到其他 生物聚合物以及许多小型有机化合物[组合 库]。合成通常通过共价连接 开始(通常是末端)残基到不溶的聚合物载体上。 该锚定步骤是整个合成计划的组成部分， 实验细节可能会对整体产生重大影响 最终产品的纯度和得率。句柄定义为 双功能间隔物，或连接体，用于实现所需的 在两个不连续的化学步骤中附着。句柄方法允许 精确控制细胞的稳定性和最终的切割 锚定连接，并便于定量连接， 避免与外来聚合物结合官能团相关的问题 组。在本研究方案的支持下，若干 句柄[PAL、(R)PAL、HAL、XAL、BAL、NPE、NONB等]和聚合物 支持[PEG-PS和Clear]已开发并应用于 挑战肽的分步缩合或分段缩合合成 目标。这些手柄/支撑组合中的一些也是合适的 用于固相有机合成。相容的Nα-氨基 [偶有NW-氨基]保护主要由酸- 不稳定的叔丁氧羰基(Boc)或不稳定的碱9- 荧甲氧羰基(Fmoc)起作用，并发生最终切割 在相对温和的条件下，副作用最小 暴露于酸、碱、光、氟离子、亲核硫醇或 在亲核受体存在下，钯(0)。取决于 实验设计，产品可以有多种端基 (通常是羧酸或羧胺)，完全自由或其他 保留侧链保护。一些试剂和程序 在本研究中开发的方案已经得到了广泛的应用 在世界各地。目前竞争性续展申请的目的是 进一步阐述这一进展，并继续展示 上述句柄可以帮助解决具有生物意义的问题 合成肽和组合化学的挑战。 同时，正在检查改进的和新的化学物质，这些化学物质可能 导致新的手柄具有更好的性能和/或更广泛的 用途。这些方法将适应一系列规模，并将 与药物发现计划和疾病诊断程序兼容 基于多路合成。

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.