Synthesis and evaluation of hermitamides A and B as human voltage-gated sodium channel blockers |
| |
Authors: | De Oliveira Eliseu O Graf Kristin M Patel Manoj K Baheti Aparna Kong Hye-Sik MacArthur Linda H Dakshanamurthy Sivanesan Wang Kan Brown Milton L Paige Mikell |
| |
Affiliation: | Drug Discovery Program, Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|