title: Synthesis and evaluation of hermitamides A and B as human voltage-gated sodium channel blockers.
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.
authors.affiliation: Drug Discovery Program, Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Eliseu O
authors.initials: EO
authors.lastname: De Oliveira
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Graf
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
authors.forename: Aparna
authors.initials: A
authors.lastname: Baheti
authors.forename: Hye-Sik
authors.initials: HS
authors.lastname: Kong
authors.forename: Linda H
authors.initials: LH
authors.lastname: MacArthur
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Kan
authors.initials: K
authors.lastname: Wang
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D007211:Indoles; D010627:Phenethylamines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C413030:hermitamide A; C413031:hermitamide B