IMPROVED HANDLES FOR SOLID-PHASE PEPTIDE SYNTHESIS

由梅里菲尔德介绍的固相法现在已被牢固地 作为一种强大的技术，用于生物学研究， 重要的肽 合成通常开始于共价连接 将所需肽的C-末端氨基酸残基转化为不溶性 聚合物载体 该锚定步骤是本发明的一个组成部分。 整体合成计划，实验细节可能会影响 显著地影响最终产物的总纯度和产率。 作为我们对实现更温和的化学方法的普遍兴趣的一部分， 肽合成，我们有几个场合，以追求 “手柄”方法锚定的优点。 句柄定义为 双功能间隔区，其用于将初始残基连接到 聚合物载体在两个不连续的步骤中。 它们允许精确控制 锚定连接的稳定性和最终断裂，以及 便于定量连接， 与外来的聚合物结合的官能团。 开发的手柄 我们的实验室与易于去除的N α-氨基 保护基如高度酸不稳定的N α-联苯基- 异丙氧基羰基（Bpoc），碱不稳定 N-α-9-芴基甲氧基羰基（Fmoc），和可硫解的 N α-二硫琥珀酰基（Dts）或N α-3-硝基-2-吡啶-硫基 （Npys）函数。 锚定键的断裂发生在 相对温和的条件与酸，光，或氟离子; 产物可以是肽酸或酰胺。 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， 制备适于纯化的部分保护的片段， 来制造更长更复杂的产品。 目前的建议旨在采取几个处理，已经 在简单的系统中计算出来，并展示了它们在应用于 挑战肽靶点。 与此同时，一些新的和改进的 化学物质的建议，可能会导致新的处理，甚至更好的 性能和/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.