TY - JOUR
T1 - 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
AU - Kudo, Yuta
AU - Yotsu-Yamashita, Mari
N1 - Funding Information:
The authors thank Mr. D. Unabara, Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, for acquiring NMR spectra using the Bruker AVANCE III 600. This work was funded by the Japan Society for the Promotion of Science (JSPS) through its Funding Program for KAKENHI Grant-in-Aid for Scientific Research nos. 26292057 and 17H03809 and Innovative Area, Frontier Research on Chemical Communications no. 17H06406 and on Redesigning Biosynthetic Machineries no. 19H04636 to M.Y.Y, and Grant-in-Aid for Research Activity start-up 18H05997 to Y.K.
Publisher Copyright:
© 2019 American Chemical Society and American Society of Pharmacognosy.
PY - 2019/6/28
Y1 - 2019/6/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85068206117&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068206117&partnerID=8YFLogxK
U2 - 10.1021/acs.jnatprod.9b00178
DO - 10.1021/acs.jnatprod.9b00178
M3 - Article
C2 - 31117524
AN - SCOPUS:85068206117
SN - 0163-3864
VL - 82
SP - 1656
EP - 1663
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 6
ER -
