TOTAL SYNTHESIS OF HUMAN INSULIN BY REGIOSELECTIVE DISULFIDE FORMATION USING THE SILYL CHLORIDE SULFOXIDE METHOD
TOTAL SYNTHESIS OF HUMAN INSULIN BY REGIOSELECTIVE DISULFIDE FORMATION USING THE SILYL CHLORIDE SULFOXIDE METHOD
复制标题
DOI：
10.1021/ja00077a043
复制
发表时间：
1993-12-01
影响因子：
15
通讯作者：
KISO, Y
中科院分区：
文献类型：
--
作者：
AKAJI, K;FUJINO, K;KISO, Y
人胰岛素是一种含有三个二硫键的双链肽，首次通过在蛋白质中顺序选择性地形成二硫键而明确地实现了全合成。合成中的关键反应是使用我们开发的氯硅烷方法单独区域选择性形成三个二硫键。在胰岛素合成之前，通过双二硫键肽、芋螺毒素M1、β-hANP和α-hANP非天然平行二聚体的合成证实，在氯硅烷处理期间没有发生二硫键交换。利用三个正交的硫醇保护基Trt、Acm和t-Bu，通过硫解、碘氧化和氯硅烷方法的连续反应，有效地构建了人胰岛素的三个二硫键。逐步形成二硫化物的每个反应都在 15-60 分钟内进行，没有聚合产物，也没有溶解度问题。合成人胰岛素具有正确的结构，与天然人胰岛素没有区别。
Total synthesis of human insulin, a two-chain peptide containing three disulfide bonds, was achieved unambiguously by sequential and selective formation of disulfide bonds in the protein for the first time. The key reaction in the synthesis is separate regioselective formation of three disulfide bonds using a silyl chloride method developed by us. Prior to the insulin synthesis, it was confirmed by the syntheses of double-disulfide peptides, conotoxin M1, beta-hANP, and an unnatural parallel dimer of alpha-hANP, that no disulfide exchange occurred during the silyl chloride treatment. Using three orthogonal thiol-protecting groups, Trt, Acm, and t-Bu, the three disulfide bonds of human insulin were efficiently constructed by successive reactions using thiolysis, iodine oxidation, and the silyl chloride method. Each reaction for the stepwise disulfide formation proceeded within 15-60 min with no polymeric product and no solubility problem. The synthetic human insulin had the correct structure and was indistinguishable from natural human insulin.