title: Synthesis of the Paralytic Shellfish Poisons (+)-Gonyautoxin 2, (+)-Gonyautoxin 3, and (+)-11,11-Dihydroxysaxitoxin.
abstract: 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.
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-0080, United States.
authors.forename: John V
authors.initials: JV
authors.lastname: Mulcahy
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-0080, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-0080, United States.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Merit
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-0080, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Whitehead
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-0080, United States.
authors.forename: J
authors.initials: J
authors.lastname: Du Bois
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D003500:Cyclization; D008387:Marine Toxins / Q000138:chemical synthesis* / Q000494:pharmacology; D009124:Muscle Proteins / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000737:chemistry; D051381:Rats; D012530:Saxitoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D012758:Shellfish; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D015222:Sodium Channels; D013237:Stereoisomerism
chemical_list: D000588:Amines; D008387:Marine Toxins; D009124:Muscle Proteins; D011758:Pyrroles; C466180:Scn4a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012530:Saxitoxin; C013007:gonyautoxins