Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels

Kanna Adachi, Tomoshi Yamada, Hayate Ishizuka, Mana Oki, Shunsuke Tsunogae, Noriko Shimada, Osamu Chiba, Tatsuya Orihara, Masafumi Hidaka, Takatsugu Hirokawa, Minami Odagi, Keiichi Konoki, Mari Yotsu-Yamashita, Kazuo Nagasawa

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2025-2033
Number of pages9
JournalChemistry - A European Journal
Volume26
Issue number9
DOIs
Publication statusPublished - 2020 Feb 11

Keywords

  • drug discovery
  • inhibitors
  • ion channels
  • membrane proteins
  • protein structures

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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