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Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV

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Science  18 Nov 2016:
Vol. 354, Issue 6314, pp. 865-869
DOI: 10.1126/science.aag2981

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Pluses and minuses of BTX behavior

Batrachotoxin is a potent neurotoxin produced by the endangered Colombian poison dart frog and is an agonist of voltage-gated sodium ion channels (NaVs). Logan et al. developed a chemical synthesis of this molecule, denoted (−)-BTX, by taking advantage of a tin hydride–mediated radical cyclization to stitch together the polycyclic framework. Using an analogous route, they also prepared the non-natural mirror image, (+)-BTX. Conversely to the natural product, (+)-BTX antagonized NaVs.

Science, this issue p. 865

Abstract

The steroidal neurotoxin (−)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (−) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate–modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (−)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of NaV. These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaV dynamics.

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