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Synthesis of C12‐Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage‐Gated Sodium Channels
Author(s) -
Adachi Kanna,
Yamada Tomoshi,
Ishizuka Hayate,
Oki Mana,
Tsunogae Shunsuke,
Shimada Noriko,
Chiba Osamu,
Orihara Tatsuya,
Hidaka Masafumi,
Hirokawa Takatsugu,
Odagi Minami,
Konoki Keiichi,
YotsuYamashita Mari,
Nagasawa Kazuo
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201904184
Subject(s) - sodium channel , saxitoxin , inhibitory postsynaptic potential , chemistry , sodium , pharmacology , biochemistry , neuroscience , toxin , medicine , biology , organic chemistry
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 Na V ‐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 EC 50 and IC 50 values of 8.5 and 30.7 n m , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin‐resistant subtype of Na V 1.5, with an IC 50 value of 94.1 n m . Derivatives 3 a – d and 3 f showed low recovery rates from Na V 1.2 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 Na V in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp 1717 .