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Isolation and Biological Activity of 8-Epitetrodotoxin and the Structure of a Possible Biosynthetic Shunt Product of Tetrodotoxin, Cep-226A, from the Newt Cynops ensicauda popei

Kudo, Yuta, Yotsu-Yamashita, Mari
Journal of natural products 2019 v.82 no.6 pp. 1656-1663
binding capacity, biosynthesis, brain, colorimetry, median effective concentration, mice, monoterpenoids, neurotoxins, rats, salamanders and newts, sodium channels, tetrodotoxin, toxicity
Tetrodotoxin (TTX, 1), a potent neurotoxin, has been found in various animal species in both marine and terrestrial environments. In this study, a new TTX analogue, 8-epiTTX (2), and a possible biosynthetic shunt compound of TTX, Cep-226A (3), were isolated from the newt Cynops ensicauda popei. The voltage-gated sodium ion channel (Naᵥ) blocking activity of 2 and 6-epiTTX (4), a known analogue, were investigated by a colorimetric cell-based assay and compared with that of 1. The EC₅₀ values for 2 and 4 were determined to be 110 ± 40 and 33 ± 11 nM, respectively, which were larger than that of 1 (1.9 ± 0.7 nM). The results indicated that the equatorial hydroxy group at C-8 in TTX significantly contributes to its Naᵥ blocking activity, whereas the 6-epimer of TTX retains substantial activity, consistent with its previously reported toxicity in mice and binding affinity to rat brain membrane preparations. The presence of these epimers of TTX (2 and 4) and Cep-226A (3) in newts supports our hypothesis that TTX is derived from a monoterpene in terrestrial environments.