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, including 11-saxitoxinethanoic acid, C13acetoxy 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 50 of 11-saxitoxinethanoic acid has been measured against rat Na V 1.4, and found to be 17.0 nM, similar to sulfated toxins gonyautoxin II and III.
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.
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 IC50 value of 11‐saxitoxinethanoic acid was measured against rat NaV1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.
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