New methods capable of effecting cyclization, and forming novel three-dimensional structures while maintaining favourable physicochemical properties are needed to facilitate the development of cyclic peptide-based drugs that can engage challenging biological targets, such as protein–protein interactions. Here, we report a highly efficient and generally applicable strategy for constructing new types of peptide macrocycles using palladium-catalysed intramolecular C(sp³)–H arylation reactions. Easily accessible linear peptide precursors of simple and versatile design can be selectively cyclized at the side chains of either aromatic or modified non-aromatic amino acid units to form various cyclophane-braced peptide cycles. This strategy provides a powerful tool to address the long-standing challenge of size- and composition-dependence in peptide macrocyclization, and generates novel peptide macrocycles with uniquely buttressed backbones and distinct loop-type three-dimensional structures. Preliminary cell proliferation screening of the pilot library revealed a potent lead compound with selective cytotoxicity toward proliferative Myc-dependent cancer cell lines.

需要新的方法来实现环化，并形成新的三维结构，同时保持良好的理化特性，以促进可参与具有挑战性的生物靶标（例如蛋白质-蛋白质相互作用）的环状肽基药物的开发。在这里，我们报告使用钯催化的分子内C（sp ^3）构建新型肽大环化合物的高效且普遍适用的策略）–H芳基化反应。简单易用的设计容易获得的线性肽前体可以在芳族或修饰的非芳族氨基酸单元的侧链上选择性环化，形成各种环烷撑开的肽环。该策略提供了一个强大的工具来解决肽大环化中长期存在的大小和成分依赖性挑战，并生成具有独特支撑骨架和独特环型三维结构的新型肽大环。对中试文库的初步细胞增殖筛选显示了一种有效的先导化合物，对增殖性Myc依赖性癌细胞系具有选择性的细胞毒性。