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

Nature Chemistry volume 10, pages 540–548 (2018)Cite this article

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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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Fig. 1: Strategy of constructing cyclophane-braced peptide macrocycles via C–H functionalization of amino acid side chains.
Fig. 2: Macrocyclization of peptides at iodinated aromatic amino acid units via Pd-catalysed intramolecular C(sp3)–H arylation.
Fig. 3: Synthesis of small-sized cyclophanes via Pd-catalysed intramolecular C(sp3)–H arylation.
Fig. 4: DFT calculation of Pd-catalysed synthesis of para-cyclophane 29.

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Acknowledgements

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.

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Authors and Affiliations

  1. 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

    Xuekai Zhang, Yanfei Ma, Mingming Zhang, Wangde Hua, Yuting Hu, Qingbing Wang, Jinghuo Chen, Gang He & Gong Chen

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Gang Lu & Peng Liu

  3. National Institute of Biological Sciences, Beijing, China

    Meng Sun & Xiangbing Qi

  4. California Institute for Biomedical Research, La Jolla, CA, USA

    Madhu Mahankali & Weijun Shen

  5. Department of Chemistry, The Pennsylvania State University, University Park, PA, USA

    Gong Chen

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  1. Xuekai Zhang
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Contributions

X.Z. carried out most of the reaction optimization and structural determination of products, and prepared the Supplementary Information. Y.M. developed peptide macrocyclization at non-aromatic amino acid units. M.Z., W.H., Y.H. and Q.W. prepared some amino acid building blocks and peptide substrates. J.C. conducted all the X-ray crystallography experiments. G.L. conducted the computations. M.M. carried out the cell proliferation assays. W.S. supervised the biological activity studies. X.Q. advised the macrocycles druggability especially the permeability optimization and directed the PAMPA assay. M.S. carried out the PAMPA assays and analysed the PAMPA data. G.H. supervised experimental studies. P.L. directed the computational studies. P.L. and G.L. prepared the computational sections of the manuscript. G.C. formulated the initial ideas of this work, supervised the project, coordinated with P.L. on computational studies, coordinated with W.S. on biological studies, and prepared most of the manuscript.

Corresponding authors

Correspondence to Gang He, Xiangbing Qi, Weijun Shen, Peng Liu or Gong Chen.

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Supplementary information

Supporting Information

Supplementary Experimental Details, Supplementary Data and Supplementary Figures.

Life Sciences Reporting Summary

Crystallographic data

Crystallographic data for compound 3a; CCDC reference: 1526698

Crystallographic data

Structure factors file for compound 3a; CCDC reference: 1526698

Crystallographic data

Crystallographic data for compound 3b; CCDC reference: 1526699

Crystallographic data

Structure factors file for compound 3b; CCDC reference: 1526699

Crystallographic data

Crystallographic data for compound 11a; CCDC reference: 1526702

Crystallographic data

Structure factors file for compound 11a; CCDC reference: 1526702

Crystallographic data

Crystallographic data for compound 17; CCDC reference: 1526701

Crystallographic data

Structure factors file for compound 17; CCDC reference: 1526701

Crystallographic data

Crystallographic data for compound 29a; CCDC reference: 1526700

Crystallographic data

Structure factors file for compound 29a; CCDC reference: 1526700

Crystallographic data

Crystallographic data for compound 29b; CCDC reference: 1526703

Crystallographic data

Structure factors file for compound 29b; CCDC reference: 1526703

Crystallographic data

Crystallographic data for compound 31a; CCDC reference: 1526704

Crystallographic data

Structure factors file for compound 31; CCDC reference: 1526704

Crystallographic data

Crystallographic data for compound 32; CCDC reference: 1526705

Crystallographic data

Structure factors file for compound 32; CCDC reference: 1526705

Crystallographic data

Crystallographic data for compound 34a; CCDC reference: 1526707

Crystallographic data

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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