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Total synthesis of the large non-ribosomal peptide polytheonamide B


An Erratum to this article was published on 01 April 2010

This article has been updated


Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC50 = 68 pg ml−1, mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30 Å in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.

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Figure 1: Structure of polytheonamide.
Figure 2: Four peptide segments for the total synthesis of polytheonamide.
Figure 3: Synthesis and structural determination of the Fmoc-protected amino acid of residue 44.
Figure 4: Solid-phase synthesis of the four peptide segments.
Figure 5: Convergent assembly of the four peptide segments.
Figure 6: Completion of the total synthesis of polytheonamide B.

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Change history

  • 23 February 2010

    In the version of this Article originally published online, an in-house error led to the incorrect representation of stereochemistry in Figs 1, 2 and 6. These have now been corrected in all versions of the Article.


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This work was supported financially by the Takeda Science Foundation and the Naito Foundation. Fellowships for N.S. and S.T. from the Japan Society for the Promotion of Science are gratefully acknowledged. We thank S. Matsunaga for providing the natural polytheonamides A and B, T. Hamada for valuable information, T. Katsuki for providing the catalyst and M. Hirama for valuable suggestions. The 800 MHz 1H NMR spectra were recorded at RIKEN SSBC, Yokohama, Japan.

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M. Inoue conceived and designed the study. N.S. and S.T. performed the total synthesis. N.S. and S.M. contributed the structural analyses. T.T., K.O., H.I., Y.M. and M.Iida performed the fragment syntheses. M.Iida and N.L. performed the bioassay. M.Inoue, N.S. and S.M. co-wrote the paper.

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Correspondence to Masayuki Inoue.

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The authors declare no competing financial interests.

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Inoue, M., Shinohara, N., Tanabe, S. et al. Total synthesis of the large non-ribosomal peptide polytheonamide B. Nature Chem 2, 280–285 (2010).

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