Tetrodotoxin: History, Biology, and Synthesis

• Published in: Angewandte Chemie International Edition 2019-12, Vol.58 (51), p.18338-18387
• Main Authors: Makarova, Mariia, Rycek, Lukas, Hajicek, Josef, Baidilov, Daler, Hudlicky, Tomas
• Format: Article
• Language: English
• Subjects: Biological activity; Biology; Biosynthesis; Drug addiction; Herbal medicine; natural products; Organic chemistry; Reviews; Sodium channels; Tetrodotoxin; total synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201901564

This review provides a comprehensive coverage of the history, biology and chemistry of tetrodotoxin (TTX). It traces the origin of this remarkable molecule all the way back to the ancient Chinese medicine records. The discovery of biological activity, isolation, and a brief overview of structure elucidation are summarized. Next, the biology of TTX is discussed, primarily in the context of its activity in the sodium channels, its anesthetic properties, and its potential use in cancer treatment or drug addiction. Biosynthesis of TTX is covered before the discussion of the total syntheses. All total, formal or partial syntheses are covered but those total syntheses that have been discussed in previous reviews are only briefly summarized. Finally, the synthesis of natural and unnatural derivatives is surveyed, and a conclusion and outlook are provided for this very extensive field of endeavor. To the best of our knowledge the literature coverage is complete up to December 2018. The deadly nature of the puffer fish has been known to mankind since the dawn of civilization. However, the compound responsible for this fatal activity was isolated only in the early 20th century and has been widely known to the scientific community as tetrodotoxin since then. This review traces its history, isolation, structural elucidation, biology, and synthesis. The syntheses of unnatural derivatives are covered as well.