Synthesis and biological evaluation of QRSTUVWXYZA′ domains of maitotoxin

K. C. Nicolaou, Philipp Heretsch, Tsuyoshi Nakamura, Anna Rudo, Michio Murata, Keiichi Konoki

    Research output: Contribution to journalArticlepeer-review

    24 Citations (Scopus)

    Abstract

    The synthesis of QRSTUVWXYZA′ domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai-Utimoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner-Wadsworth-Emmons coupling of WXYZA′ ketophosphonate 11 with QRSTU aldehyde 12 to form enone 10, and a reductive hydroxyketone ring closure to forge ring V. 2D NMR spectroscopic analysis and comparison of 13C chemical shifts with those of the corresponding carbons of maitotoxin revealed close similarities supporting the originally assigned structure of this region of the natural product. Biological evaluations of various synthesized domains of maitotoxin in this and previous studies from these laboratories led to fragment structure-activity relationships regarding their ability to inhibit maitotoxin-elicited Ca2+ influx in rat C6 glioma cells.

    Original languageEnglish
    Pages (from-to)16444-16451
    Number of pages8
    JournalJournal of the American Chemical Society
    Volume136
    Issue number46
    DOIs
    Publication statusPublished - 2014 Nov 19

    ASJC Scopus subject areas

    • Catalysis
    • Chemistry(all)
    • Biochemistry
    • Colloid and Surface Chemistry

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