Toxic aromatic compounds from fruits of Narthecium ossifragum L

The intake of Narthecium ossifragum, commonly known as bog asphodel, has been associated with toxic effects observed in sheep for centuries. Although the plant has been studied for five centuries little is known about its chemical constituents. Six previously undescribed natural products, naringenin(3 → 6″)luteolin, naringenin(3 → 6″)chrysoeriol, liovil 4-O-β-glucopyranoside, 2,6-dimethoxy cinnamic acid, (E)-4-(3-hydroxy-2,2-dimethylchroman-6-yl)but-3-en-2-one and (E)-4-(4-(((E)-4-hydroxy-3-methylbut-2-en-1-yl)oxy)phenyl)but-3-en-2-one, have been identified from fruits of N. ossifragum for the first time. In addition, the rare natural product 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde and the five known compounds 4-hydroxycinnamic acid, quercetin 3,3'-dimethyl ether, quercetin 3,7-dimethyl ether, chrysoeriol 7-O-β-glucopyranoside and the di-C-glycosylflavone isoschaftoside were all characterized for the first time from the fruits of N. ossifragum. The discovery of sufficient amounts of 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde in fresh plant material of N. ossifragum to allow complete structure elucidation by NMR and HRMS supports the possibility that fungi associated with N. ossifragum may be able to produce enough toxins to play a significant role in the pathogenicity of N. ossifragum. 4-Hydroxy-3-(3-methylbut-2-enyl)benzaldehyde showed mild toxicity towards normal rat kidney (NRK) and more profound activity towards MOLM13 acute myeloid leukemia cells (IC₅₀ = 430 μM and 68 μM, respectively). Naringenin(3 → 6″)luteolin had IC₅₀ of 230 μM towards NRK cells, and 115 μM towards MOLM13 cells. Microscopic evaluation suggests that these two compounds induce cell death by different mechanisms.