Title |
A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp3 C−H arylation
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Published in |
Nature Chemistry, April 2018
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DOI | 10.1038/s41557-018-0006-y |
Pubmed ID | |
Authors |
Xuekai Zhang, Gang Lu, Meng Sun, Madhu Mahankali, Yanfei Ma, Mingming Zhang, Wangde Hua, Yuting Hu, Qingbing Wang, Jinghuo Chen, Gang He, Xiangbing Qi, Weijun Shen, Peng Liu, Gong Chen |
Abstract |
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. |
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