Exploring the structural basis of neurotoxicity in C-17-polyacetylenes isolated from water hemlock

Water hemlock, Cicuta virosa, belonging to the Umbelliferae, is well-known as a toxic plant responsible for lethal poisonings in humans as well as ani mals, causing tonic and clonic convulsions and respiratory paralysis. Cicut oxin (1), being a major violent toxin of the plant, is a chemical in the cl ass of C-17-polyacetylenes bearing a long;c-bond conjugation system, a term inal hydroxyl, and an allylic hydroxyl in its structure, and a variety of i fs analogues have been isolated from the plant. In the present study, vario us derivatives of these toxins were synthesized through acetylation, methyl ation, and oxidation of cicutoxin(1) and virol A (3) and B (4). 1-Dehydroxy virol 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 co mpound (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 invo lved in the acute toxicity of cicutoxin derivatives in mice were investigat ed, and the length and geometry of rr-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, [H-3]EBOB, t o GABA-gated Cl- channels of GABA receptors in rat brain cortex was found t o be correlated with acute toxicity, indicating that the ability to bind to these channels plays an important role in the acute toxicity of these comp ounds.