Synthesis of the Paralytic Shellfish Poisons (+)-Gonyautoxin 2, (+)-Gonyautoxin 3, and (+)-11,11-Dihydroxysaxitoxin

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• 作者：John V. Mulcahy ; James R. Walker ; Jeffrey E. Merit ; Alan Whitehead ; J. Du Bois
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：May 11, 2016
• 年：2016
• 卷：138
• 期：18
• 页码：5994-6001
• 全文大小：546K
• 年卷期：0
• ISSN：1520-5126

文摘

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 Na_V1.4, and are found to be 22 nM, 15 nM, and 2.2 μM, respectively.