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Synthesis and biological evaluation of QRSTUVWXYZA' domains of maitotoxin

Academic Article
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Overview

authors

  • Nicolaou, K.C.
  • Heretsch, P.
  • Nakamura, T.
  • Rudo, A.
  • Murata, M.
  • Konoki, K.

publication date

  • November 2014

journal

  • Journal of the American Chemical Society  Journal

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 (13)C 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 Ca(2+) influx in rat C6 glioma cells.

subject areas

  • Aldehydes
  • Amino Acid Sequence
  • Animals
  • Calcium
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Humans
  • Marine Toxins
  • Organophosphonates
  • Oxocins
  • Peptide Fragments
  • Protein Structure, Tertiary
  • Rats
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Identity

PubMed Central ID

  • PMC4244842

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja509829e

PubMed ID

  • 25374117
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Additional Document Info

start page

  • 16444

end page

  • 16451

volume

  • 136

issue

  • 46

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