RESUMO
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 .
Assuntos
Saxitoxina/química , Bloqueadores dos Canais de Sódio/síntese química , Canais de Sódio Disparados por Voltagem/metabolismo , Potenciais de Ação/efeitos dos fármacos , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Técnicas de Patch-Clamp , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Teoria Quântica , Saxitoxina/metabolismo , Saxitoxina/farmacologia , Bloqueadores dos Canais de Sódio/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/química , Tetrodotoxina/metabolismo , Canais de Sódio Disparados por Voltagem/química , Canais de Sódio Disparados por Voltagem/genéticaRESUMO
11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C-C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4 N][Ph3 SnF2 ], which directly constructs the crucial C-C bond at the C11 position in SEA. The NaV Ch-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50 value of (47±12)â nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).
