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

Nature Chemistryvolume 10pages540548 (2018) | Download Citation

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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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.

Author information

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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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.

Competing interests

The authors declare no competing interests.

Corresponding authors

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

Supplementary information

  1. Supporting Information

    Supplementary Experimental Details, Supplementary Data and Supplementary Figures.

  2. Life Sciences Reporting Summary

  3. Crystallographic data

    Crystallographic data for compound 3a; CCDC reference: 1526698

  4. Crystallographic data

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

  5. Crystallographic data

    Crystallographic data for compound 3b; CCDC reference: 1526699

  6. Crystallographic data

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

  7. Crystallographic data

    Crystallographic data for compound 11a; CCDC reference: 1526702

  8. Crystallographic data

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

  9. Crystallographic data

    Crystallographic data for compound 17; CCDC reference: 1526701

  10. Crystallographic data

    Structure factors file for compound 17; CCDC reference: 1526701

  11. Crystallographic data

    Crystallographic data for compound 29a; CCDC reference: 1526700

  12. Crystallographic data

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

  13. Crystallographic data

    Crystallographic data for compound 29b; CCDC reference: 1526703

  14. Crystallographic data

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

  15. Crystallographic data

    Crystallographic data for compound 31a; CCDC reference: 1526704

  16. Crystallographic data

    Structure factors file for compound 31; CCDC reference: 1526704

  17. Crystallographic data

    Crystallographic data for compound 32; CCDC reference: 1526705

  18. Crystallographic data

    Structure factors file for compound 32; CCDC reference: 1526705

  19. Crystallographic data

    Crystallographic data for compound 34a; CCDC reference: 1526707

  20. Crystallographic data

    Structure factors file for compound 34a; CCDC reference: 1526707

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DOI

https://doi.org/10.1038/s41557-018-0006-y