Synthesis and biological evaluation of QRSTUVWXYZA' domains of maitotoxin.
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.
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
K C
KC
Nicolaou
Philipp
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Heretsch
Tsuyoshi
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Nakamura
Anna
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Rudo
Michio
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Murata
Keiichi
K
Konoki
D000447:Aldehydes / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D008387:Marine Toxins / Q000737:chemistry* / Q000633:toxicity; D063065:Organophosphonates / Q000737:chemistry; D035964:Oxocins / Q000737:chemistry* / Q000633:toxicity; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D000095702:Polyether Toxins
D000447:Aldehydes; D002118:Calcium; D008387:Marine Toxins; D063065:Organophosphonates; D035964:Oxocins; D010446:Peptide Fragments; C020394:maitotoxin; D000095702:Polyether Toxins