The University of Tokyo, Tokyo 113-0033, Japan.
Nat Chem. 2010 Apr;2(4):280-5. doi: 10.1038/nchem.554. Epub 2010 Feb 21.
Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC(50) = 68 pg ml(-1), mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30 Å in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.
聚醚酰胺 B 是目前已知的最大的非核糖体肽，具有非凡的细胞毒性（EC（50）= 68pg/ml，P388 白血病细胞）。它的 48 个氨基酸残基包括各种非蛋白氨基酸的 d-和 l-氨基酸，并且这些氨基酸的绝对立体化学在序列中交替。这些结构特征诱导形成稳定的β-折叠型结构，从而形成超过 30Å 的整体管状结构。在生物环境中，这种折叠被认为通过孔将阳离子运输穿过脂双层，从而作为离子通道起作用。在这里，我们报告了聚醚酰胺 B 的首次化学构建。我们的合成依赖于四个关键阶段的组合：非蛋白氨基酸的合成、聚醚酰胺 B 的四个片段的固相组装、片段的银介导连接，以及最终的全局去保护。现在可用的合成材料将允许研究其构象特性、通道功能和细胞毒性之间的关系。
