RESUMO
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.
Assuntos
Amidas/farmacologia , Indóis/farmacologia , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Amidas/síntese química , Amidas/química , Linhagem Celular , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Conformação Molecular , Fenetilaminas/síntese química , Fenetilaminas/química , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Canais de Sódio/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
