Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels.
Chemistry
; 26(9): 2025-2033, 2020 Feb 11.
Article
en En
| MEDLINE
| ID: mdl-31769085
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 Neuroâ
2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7â
nm, respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV 1.5, with an IC50 value of 94.1â
nm. Derivatives 3 a-d and 3 f showed low recovery rates from NaV 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 NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717 .
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Saxitoxina
/
Bloqueadores de los Canales de Sodio
/
Canales de Sodio Activados por Voltaje
Límite:
Humans
Idioma:
En
Revista:
Chemistry
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Japón