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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G.C. thanks the State Key Laboratory of Elemento-Organic Chemistry at Nankai University, NSFC-21672105, NSFC-21421062, the ‘111’ project (B06005) of the Ministry of Education of China, and programme 973 (2014CB849603 to X.Q.) for financial support of the experimental part of this work. P.L. thanks the University of Pittsburgh for financial support for the computational part of the work. Calculations were performed at the Center for Simulation and Modeling at the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science Foundation. W.S. and M.M. thank M. Hull, M. Wogan, H. Nguyen and E. Chen of Calibr for technical support and help. G.C. dedicates this work to Q. Zhou on the occasion of his 60th birthday.
The authors declare no competing interests.
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Supplementary Experimental Details, Supplementary Data and Supplementary Figures.
Crystallographic data for compound 3a; CCDC reference: 1526698
Structure factors file for compound 3a; CCDC reference: 1526698
Crystallographic data for compound 3b; CCDC reference: 1526699
Structure factors file for compound 3b; CCDC reference: 1526699
Crystallographic data for compound 11a; CCDC reference: 1526702
Structure factors file for compound 11a; CCDC reference: 1526702
Crystallographic data for compound 17; CCDC reference: 1526701
Structure factors file for compound 17; CCDC reference: 1526701
Crystallographic data for compound 29a; CCDC reference: 1526700
Structure factors file for compound 29a; CCDC reference: 1526700
Crystallographic data for compound 29b; CCDC reference: 1526703
Structure factors file for compound 29b; CCDC reference: 1526703
Crystallographic data for compound 31a; CCDC reference: 1526704
Structure factors file for compound 31; CCDC reference: 1526704
Crystallographic data for compound 32; CCDC reference: 1526705
Structure factors file for compound 32; CCDC reference: 1526705
Crystallographic data for compound 34a; CCDC reference: 1526707
Structure factors file for compound 34a; CCDC reference: 1526707
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Zhang, X., Lu, G., Sun, M. et al. A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp3 C−H arylation. Nature Chem 10, 540–548 (2018). https://doi.org/10.1038/s41557-018-0006-y
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