ABSTRACT
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.
Subject(s)
Amides/pharmacology , Indoles/pharmacology , Phenethylamines/pharmacology , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Amides/chemical synthesis , Amides/chemistry , Cell Line , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Conformation , Phenethylamines/chemical synthesis , Phenethylamines/chemistry , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
