Department of Chemistry, Stanford University , Stanford, California 94305-0080, United States.
J Am Chem Soc. 2016 May 11;138(18):5994-6001. doi: 10.1021/jacs.6b02343. Epub 2016 May 3.
The paralytic shellfish poisons are a collection of guanidine-containing natural products that are biosynthesized by prokaryote and eukaryote marine organisms. These compounds bind and inhibit isoforms of the mammalian voltage-gated Na(+) ion channel at concentrations ranging from 10(-11) to 10(-5) M. Here, we describe the de novo synthesis of three paralytic shellfish poisons, gonyautoxin 2, gonyautoxin 3, and 11,11-dihydroxysaxitoxin. Key steps include a diastereoselective Pictet-Spengler reaction and an intramolecular amination of an N-guanidyl pyrrole by a sulfonyl guanidine. The IC50's of GTX 2, GTX 3, and 11,11-dhSTX have been measured against rat NaV1.4, and are found to be 22 nM, 15 nM, and 2.2 μM, respectively.
麻痹性贝类毒素是一组胍基化合物天然产物，由原核生物和真核海洋生物生物合成。这些化合物在浓度为 10(-11) 到 10(-5) M 的范围内结合并抑制哺乳动物电压门控 Na(+)离子通道的同工型。在这里，我们描述了三种麻痹性贝类毒素——GTX2、GTX3 和 11,11-二羟基石房蛤毒素的从头合成。关键步骤包括立体选择性的 Pictet-Spengler 反应和亚磺酰胍的 N-胍基吡咯的分子内胺化。GTX2、GTX3 和 11,11-dhSTX 的 IC50 值已针对大鼠 NaV1.4 进行了测量，分别为 22 nM、15 nM 和 2.2 μM。
