IMPROVED HANDLES FOR SOLID-PHASE PEPTIDE SYNTHESIS

由Merrifield提出的固相法现在是坚定的 作为生物学研究的有力技术而建立起来的 重要的多肽。合成通常以共价的方式开始 所需多肽的C端氨基酸残基为不溶的 聚合物载体。这一锚定步骤是 总体综合计划，以及实验细节可能会影响 对最终产品的总体纯度和产率有显著影响。 作为我们实现更温和的化学方法的普遍兴趣的一部分 多肽合成，我们已经有过几次追寻 “手柄”锚定方法的优势。句柄定义为 用于将初始残基连接到 聚合物支撑体分两步进行。它们允许精确控制 锚定连杆的稳定性和最终劈裂，以及 促进量化依恋，避免相关问题 具有无关的聚合物结合官能团。手柄开发于 我们的实验室与易于拆卸的N-α-氨基兼容 保护基团，如高度不稳定的N-α-联苯基- 碱不稳定的异丙氧羰基(BPOC) N-α-9-荧甲氧基羰基(Fmoc)及其硫解物 Nα-二硫代琥珀酰基(DTS)或Nα-3-硝基-2-吡啶-亚磺基 (Npys)函数。锚定连杆的断裂发生在 具有酸、光或氟离子的相对温和的条件； 产品可以是多肽酸或酰胺。这些手柄的应用 在正交保护方案中提供了进一步的可能性 后续制备适合纯化的部分保护片段 通过重新缝合来制造更长、更复杂的产品。 目前的建议旨在采取几个已经 在简单的系统中计算，并演示它们的应用范围 具有挑战性的多肽目标。同时，一些修改过的和新的 建议进行化学处理，可能会产生新的处理，甚至更好 属性和/或更广泛的应用。

The solid-phase method introduced by Merrifield is now firmly established as a powerful technique for the study of biologically important peptides. Synthesis normally begins by covalently liking the C-terminal amino acid residue of the desired peptide 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. As part of our general interest in achieving milder chemical methods for peptide synthesis, we have had several occasions to pursue the advantages of "handle" approaches to anchoring. Handles are defined as bifunctional spacers which serve to attach the initial residue to the polymeric support in two discrete steps. They allow precise control over the stability and ultimate cleavage of the anchoring linkage, and facilitate quantitative attachments which circumvent problems associated with extraneous polymer-bound functional groups. Handles developed in our laboratory are compatible with readily removable N alpha-amino protecting groups such as the highly acid-labile N alpha-biphenylyl- isopropyloxycarbonyl (Bpoc), the base-labile N alpha-9-fluorenylmethyloxycarbonyl (Fmoc), and the thiolysable N alpha-dithiasuccinoyl (Dts) or N alpha-3-nitro-2-pyridine-sulfenyl (Npys) functions. Cleavages of the anchoring linkages occur under relatively mild conditions with acid, light, or fluoride ion; the products may be peptide acids or amides. Application of these handles in orthogonal protection schemes offers the further possibility of preparing partially protected segment suitable for purification followed by restitching to make longer and more complicated products. The present proposal aims to take several handles that have already been worked out in simple systems and demonstrate their scope when applied to challenging peptide targets. Simultaneously, some modified and new chemistries are suggested that may lead to new handles with even better properties and/or a wider range of applications.