作为人类电压门控钠离子通道阻断剂的隐士酰胺 A 和 B 的合成与评价。
Synthesis and evaluation of hermitamides A and B as human voltage-gated sodium channel blockers.
机构信息
Drug Discovery Program, Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
出版信息
Bioorg Med Chem. 2011 Jul 15;19(14):4322-9. doi: 10.1016/j.bmc.2011.05.043. Epub 2011 May 30.
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.
摘要
海兔肽 A 和 B 是从巴布亚新几内亚产的海洋蓝藻 Lyngbya majuscula 中分离得到的脂肽。我们推测，海兔肽类似于 Jamaicamides，可能是人类电压门控钠离子通道 (hNa(V)) 的配体。在此，我们描述了海兔肽 A 和 B 及其差向异构体的非对映体全合成。我们报道了海兔肽在 10 μM 浓度下比临床使用的钠离子通道阻滞剂苯妥英更有效地置换 [(3)H]-BTX。我们还提出了 (S)-海兔肽 B 在 BTX 结合部位的可能结合模式和电生理学研究，表明这些化合物是 hNav1.2 电压门控钠离子通道的有效阻断剂。
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