SAFC, Inc., 645 Science Dr., Madison, WI, 53711, USA.
Gilead Sciences, 333 Lakeside Dr., Foster City, CA, 94404, USA.
Angew Chem Int Ed Engl. 2019 Feb 4;58(6):1689-1693. doi: 10.1002/anie.201811717. Epub 2019 Jan 2.
The bis-guanidinium toxins are a collection of natural products that display nanomolar potency against select isoforms of eukaryotic voltage-gated Na ion channels. We describe a synthetic strategy that enables access to four of these poisons, namely 11-saxitoxinethanoic acid, C13-acetoxy saxitoxin, decarbamoyl saxitoxin, and saxitoxin. Highlights of this work include an unusual Mislow-Evans rearrangement and a late-stage Stille ketene acetal coupling. The IC value of 11-saxitoxinethanoic acid was measured against rat Na 1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.
双胍毒素是一组天然产物,对真核电压门控 Na 离子通道的某些同工型具有纳摩尔效力。我们描述了一种合成策略,可获得其中的四种毒素,即 11-石房蛤毒素乙醇酸、C13-乙酰氧基石房蛤毒素、脱氨甲酰石房蛤毒素和石房蛤毒素。这项工作的重点包括不寻常的 Mislow-Evans 重排和晚期的 Stille 酮烯醇缩合。11-石房蛤毒素乙醇酸对大鼠 Na 1.4 的 IC 值进行了测量,发现为 17.0nm,与硫酸化毒素 GTX2 和 GTX3 的相似。