Exploring the structural basis of neurotoxicity in C17-polyacetylenes isolated from water hemlock

K. Uwai, K. Ohashi, Y. Takaya, T. Ohta, T. Tadano, K. Kisara, K. Shibusawa, R. Sakakibara, Y. Oshima

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Water hemlock, Cicuta virosa, belonging to the Umbelliferae, is well-known as a toxic plant responsible for lethal poisonings in humans as well as animals, causing tonic and clonic convulsions and respiratory paralysis. Cicutoxin (1), being a major violent toxin of the plant, is a chemical in the class of C17-polyacetylenes bearing a long π-bond conjugation system, a terminal hydroxyl, and an allylic hydroxyl in its structure, and a variety of its analogues have been isolated from the plant. In the present study, various derivatives of these toxins were synthesized through acetylation, methylation, and oxidation of cicutoxin (1) and virol A (3) and B (4). 1-Dehydroxyvirol A (28) was prepared through the coupling of (7S)-dodeca-3,5-dien-1-yn-7-ol and 1-iodopentyne under Sonogashira's conditions. A monoacetylenic compound (29) was also prepared through the coupling of (5S)-1-chlorodeca-1,3-dien-5-ol and 1-iodopentyn-5-ol. The structure-activity relationships involved in the acute toxicity of cicutoxin derivatives in mice were investigated, and the length and geometry of π-bond conjugation and the O-functional groups were found to be important for activity. The potency in inhibition of the specific binding of the noncompetitive GABA antagonist, [3H]EBOB, to GABA-gated Cl- channels of GABA receptors in rat brain cortex was found to be correlated with acute toxicity, indicating that the ability to bind to these channels plays an important role in the acute toxicity of these compounds.

Original languageEnglish
Pages (from-to)4508-4515
Number of pages8
JournalJournal of Medicinal Chemistry
Volume43
Issue number23
DOIs
Publication statusPublished - 2000 Nov 16

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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