A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp3 C-H arylation

作者：Zhang, Xuekai; Lu, Gang; Sun, Meng; Mahankali, Madhu; Ma, Yanfei; Zhang, Mingming; Hua, Wangde; Hu, Yuting; Wang, Qingbing; Chen, Jinghuo; He, Gang^*; Qi, Xiangbing^*; Shen, Weijun^*; Liu, Peng^*; Chen, Gong^*

来源：Nature Chemistry, 2018, 10(5): 540-548.

DOI：10.1038/s41557-018-0006-y

• CARBON-HYDROGEN BONDS
• C(SP(3))-H ACTIVATION
• NATURAL-PRODUCTS
• AMINO-ACIDS
• COUPLING REACTIONS
• CYCLIC-PEPTIDES
• FUNCTIONALIZATION
• METATHESIS
• SCAFFOLDS
• CHEMISTRY

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(3))-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.

• 出版日期2018-5
• 单位北京生命科学研究所; 南开大学