@article{1b7f7025712c4f34b00d69745c9ff011,
title = "Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels",
abstract = "A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV-inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX (3 a) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm, respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV1.5, with an IC50 value of 94.1 nm. Derivatives 3 a–d and 3 f showed low recovery rates from NaV1.2 subtype (ca 45–79 %) compared to natural dcSTX (2), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717.",
keywords = "drug discovery, inhibitors, ion channels, membrane proteins, protein structures",
author = "Kanna Adachi and Tomoshi Yamada and Hayate Ishizuka and Mana Oki and Shunsuke Tsunogae and Noriko Shimada and Osamu Chiba and Tatsuya Orihara and Masafumi Hidaka and Takatsugu Hirokawa and Minami Odagi and Keiichi Konoki and Mari Yotsu-Yamashita and Kazuo Nagasawa",
note = "Funding Information: This research was funded by Grants-in-Aid for Scientific Research on Innovative Areas “Middle Molecular Strategy” (18H04387 to K.N.), “Frontier Research on Chemical Communications” from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan (JP17H06406 to K.K. and M.Y.-Y.), Grants-in-Aid for Scientific Research (B) (JP17H02199 to K.K. and JPH03809 to M.Y.-Y.), the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from the Japan Agency for Medical Research and Development (AMED, JP18am0101114) and MEXT as “Priority Issue on Post-K computer” (Building Innovation Drug Discovery Infrastructure Through Functional Control of Biomolecular Systems) (hp160213) (T.H.), and a grant from the Naito Foundation (K.K.). K.A. thanks SUNBOR for providing a scholarship. The authors thank the Riken Bioresource Center through the National Bio-Resource Project of the MEXT, Japan, for supplying human embryonic kidney cell line 293T (RCB2202). The authors are also grateful to Professor Minoru Wakamori, Graduate School of Dentistry, Tohoku University, for technical assistance. This work was inspired by the international and interdisciplinary environment of the JSPS Asian CORE Program of ACBI (Asian Chemical Biology Initiative). Funding Information: This research was funded by Grants‐in‐Aid for Scientific Research on Innovative Areas “Middle Molecular Strategy” (18H04387 to K.N.), “Frontier Research on Chemical Communications” from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan (JP17H06406 to K.K. and M.Y.‐Y.), Grants‐in‐Aid for Scientific Research (B) (JP17H02199 to K.K. and JPH03809 to M.Y.‐Y.), the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from the Japan Agency for Medical Research and Development (AMED, JP18am0101114) and MEXT as “Priority Issue on Post‐K computer” (Building Innovation Drug Discovery Infrastructure Through Functional Control of Biomolecular Systems) (hp160213) (T.H.), and a grant from the Naito Foundation (K.K.). K.A. thanks SUNBOR for providing a scholarship. The authors thank the Riken Bioresource Center through the National Bio‐Resource Project of the MEXT, Japan, for supplying human embryonic kidney cell line 293T (RCB2202). The authors are also grateful to Professor Minoru Wakamori, Graduate School of Dentistry, Tohoku University, for technical assistance. This work was inspired by the international and interdisciplinary environment of the JSPS Asian CORE Program of ACBI (Asian Chemical Biology Initiative). Publisher Copyright: {\textcopyright} 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",
year = "2020",
month = feb,
day = "11",
doi = "10.1002/chem.201904184",
language = "English",
volume = "26",
pages = "2025--2033",
journal = "Chemistry - A European Journal",
issn = "0947-6539",
publisher = "Wiley-VCH Verlag",
number = "9",
}