State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Chem. 2018 May;10(5):540-548. doi: 10.1038/s41557-018-0006-y. Epub 2018 Apr 2.
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(sp)-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，同时在保持有利的物理化学性质的情况下形成新颖的三维结构，以促进基于环状肽的药物的开发，这些药物可以与具有挑战性的生物靶点（如蛋白质-蛋白质相互作用）结合。在这里，我们报告了一种使用钯催化的分子内 C(sp)-H 芳基化反应构建新型肽大环的高效且通用的策略。可通过选择在芳族或修饰的非芳族氨基酸单元的侧链处环化，从而将易于获得的简单且通用设计的线性肽前体选择性地环化，形成各种具有芳环支撑的肽环。该策略为解决肽大环化中大小和组成依赖性的长期挑战提供了一种强大的工具，并生成了具有独特支撑骨架和独特环型三维结构的新型肽大环。对先导文库的初步细胞增殖筛选揭示了一种具有选择性细胞毒性的潜在先导化合物，对增殖的 Myc 依赖性癌细胞系具有选择性。
