Total synthesis of the large non-ribosomal peptide polytheonamide B

Masayuki Inoue, Naoki Shinohara, Shintaro Tanabe, Tomoaki Takahashi, Ken Okura, Hiroaki Itoh, Yuki Mizoguchi, Maiko Iida, Nayoung Lee, Shigeru Matsuoka

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    62 Citations (Scopus)

    Abstract

    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 30Å 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.

    Original languageEnglish
    Pages (from-to)280-285
    Number of pages6
    JournalNature Chemistry
    Volume2
    Issue number4
    DOIs
    Publication statusPublished - 2010 Apr

    ASJC Scopus subject areas

    • Chemistry(all)
    • Chemical Engineering(all)

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  • Cite this

    Inoue, M., Shinohara, N., Tanabe, S., Takahashi, T., Okura, K., Itoh, H., Mizoguchi, Y., Iida, M., Lee, N., & Matsuoka, S. (2010). Total synthesis of the large non-ribosomal peptide polytheonamide B. Nature Chemistry, 2(4), 280-285. https://doi.org/10.1038/nchem.554