A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp 3 C-H arylation

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

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

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(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.

Original languageEnglish (US)
Pages (from-to)540-548
Number of pages9
JournalNature Chemistry
Volume10
Issue number5
DOIs
StatePublished - May 1 2018

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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