RESUMEN
Hermitamides A and B are lipopeptides isolated from a Papau New Guinea collection of the marine cyanobacterium Lyngbya majuscula. We hypothesized that the hermitamides are ligands for the human voltage-gated sodium channel (hNa(V)) based on their structural similarity to the jamaicamides. Herein, we describe the nonracemic total synthesis of hermitamides A and B and their epimers. We report the ability of the hermitamides to displace [(3)H]-BTX at 10 µM more potently than phenytoin, a clinically used sodium channel blocker. We also present a potential binding mode for (S)-hermitamide B in the BTX-binding site and electrophysiology showing that these compounds are potent blockers of the hNav1.2 voltage-gated sodium channel.
Asunto(s)
Amidas/farmacología , Indoles/farmacología , Fenetilaminas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Amidas/síntesis química , Amidas/química , Línea Celular , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Conformación Molecular , Fenetilaminas/síntesis química , Fenetilaminas/química , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The jamaicamides are natural product sodium channel blockers derived from the cyanobacterium Lyngbya majuscula. The carboxylic acid fragment of jamaicamide C contains a methyl stereocenter and a trisubstituted E chloroolefin. Herein, we present the nonracemic synthesis of the aliphatic chain of jamaicamide C. The methyl stereocenter was installed using Evans' oxazolidinone methodology, and the trisubstituted chloroolefin was set by silylstannylation of a triple bond.