Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against Na V

• Published in: Science (American Association for the Advancement of Science) 2016-11, Vol.354 (6314), p.865-869
• Main Authors: Logan, Matthew M., Toma, Tatsuya, Thomas-Tran, Rhiannon, Du Bois, J.
• Format: Article
• Language: English
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aag2981

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 Syntheses of a neurotoxin and its unnatural mirror image reveal their opposite biochemical effects. The steroidal neurotoxin (−)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (Na V s). 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 Na V 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 Na V . These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate Na V dynamics.