Characterization of the Preferred Stereochemistry for the Neuropharmacologic Actions of Antillatoxin

W. I. Li, B. L. Marquez, T. Okino, F. Yokokawa, T. Shioiri, W. H. Gerwick, Thomas F. Murray

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Antillatoxin is a potent ichthyotoxin and cytotoxin previously discovered from the marine cyanobacterium Lyngbya majuscula. Ensuing studies of its mechanism of action showed it to activate the mammalian voltage-gated sodium channel at a pharmacological site that is distinct from any previously described. The structure of antillatoxin, initially formulated from spectroscopic information, was subsequently corrected at one stereocenter (C-4) as a result of synthesis of four different antillatoxin stereoisomers (all possible C-4 and C-5 diastereomers). In the current study these four stereoisomers, (4R,5R)-, (4S,5R)-, (4S,5S)-, and (4R,5S)-antillatoxin, were characterized in five different biological assay systems: ichthyotoxicity to goldfish, microphysiometry using cerebellar granule cells (CGCs), lactose dehydrogenase efflux from CGCs, monitoring of intracellular Ca2+ concentrations in CGCs, and cytotoxicity to Neuro 2a cells. Across these various biological measures there was great consistency in that the natural antillatoxin (the 4R,5R-isomer) was greater than 25-fold more potent than any of the other stereoisomers. Detailed NMR studies provided a number of torsion and distance constraints that were modeled using the MM2* force field to yield predicted solution structures of the four antillatoxin stereoisomers. The macrocycle and side chain of natural (4R,5R)-antillatoxin present an overall "L-shaped" topology with an accumulation of polar substituents on the external surface of the macrocycle and a hydrogen bond between N(H)-7′ and the C(O)-1 carbonyl. The decreased potency of the three non-naturally occurring antillatoxin stereoisomers is certainly a result of their dramatically altered overall molecular topologies.

Original languageEnglish
Pages (from-to)559-568
Number of pages10
JournalJournal of Natural Products
Volume67
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Fingerprint

stereoisomers
Stereochemistry
stereochemistry
Stereoisomerism
granules
topology
ichthyotoxins
Moorea producens
cells
cytotoxins
diastereomers
sodium channels
goldfish
Topology
hydrogen
lactose
isomers
cytotoxicity
Cyanobacteria
Voltage-Gated Sodium Channels

All Science Journal Classification (ASJC) codes

  • Plant Science
  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Characterization of the Preferred Stereochemistry for the Neuropharmacologic Actions of Antillatoxin. / Li, W. I.; Marquez, B. L.; Okino, T.; Yokokawa, F.; Shioiri, T.; Gerwick, W. H.; Murray, Thomas F.

In: Journal of Natural Products, Vol. 67, No. 4, 04.2004, p. 559-568.

Research output: Contribution to journalArticle

Li, W. I. ; Marquez, B. L. ; Okino, T. ; Yokokawa, F. ; Shioiri, T. ; Gerwick, W. H. ; Murray, Thomas F. / Characterization of the Preferred Stereochemistry for the Neuropharmacologic Actions of Antillatoxin. In: Journal of Natural Products. 2004 ; Vol. 67, No. 4. pp. 559-568.
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