Synthesis and biological evaluation of QRSTUVWXYZA' domains of maitotoxin.

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.

• Authors: K C Nicolaou, Philipp Heretsch, Tsuyoshi Nakamura, Anna Rudo, Michio Murata, Keiichi Konoki
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 136 Issue 46 Pg. 16444-51 (Nov 19 2014) ISSN: 1520-5126 [Electronic] United States
• PMID: 25374117 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Marine Toxins
• Organophosphonates
• Oxocins
• Peptide Fragments
• maitotoxin
• Calcium

Topics

• Aldehydes (chemistry)
• Amino Acid Sequence
• Animals
• Calcium (metabolism)
• Cell Line, Tumor
• Chemistry Techniques, Synthetic
• Humans
• Marine Toxins (chemistry, toxicity)
• Organophosphonates (chemistry)
• Oxocins (chemistry, toxicity)
• Peptide Fragments (chemical synthesis, chemistry, pharmacology)
• Protein Structure, Tertiary
• Rats