Seed Dormancy Breaking Diterpenoids from the Liverwort <i>Plagiochila sciophila</i> and their Differentiation Inducing Activity in Human Promyelocytic Leukemia HL-60 Cells

<jats:p> To obtain the structural diversity of bioactive compounds similar to cotylenins and fusicoccins that modulate 14-3-3 protein-protein interactions in eukaryotes, screening tests were carried out using the lettuce seed dormancy breaking-assay. An acetone extract of the liverwort Plagiochila sciophila exhibited significant activity against the seeds in the presence of the plant hormone abscisic acid. Activity-guided fractionation of the extract afforded the isolation of seven novel fusicoccane-type diterpenoids, named fusicosciophins A-E (1–5), 8-deacetyl (6) and 9-deacetyl fusicosciophin E (7). Their structures were determined by spectroscopic methods and X-ray crystallographic analyses. All the pure isolated compounds (1–7) exhibited moderate lettuce seed dormancy breaking activity. In addition, the differentiation-inducing activity and cytotoxicity of these isolates, together with fusicoccin A (FC-A) and all- trans retinoic acid (ATRA), were evaluated in human promyelocytic leukemia HL-60 cells and human mouth epidermal carcinoma KB cells, respectively. Fusicosciophins (2 and 4) and FC-A exhibited moderate differentiation-inducing activity (EC<jats:sub>50</jats:sub> 31.2~59.1μM) compared with ATRA (EC<jats:sub>50</jats:sub> 0.3μM), while 2, 4 and ATRA exhibited higher selectivity indices (IC<jats:sub>50</jats:sub>/EC<jats:sub>50</jats:sub> >3.38~667) than FC-A (IC<jats:sub>50</jats:sub>/EC<jats:sub>50</jats:sub> 1.05). This is the first report on the isolation of fusicoccane-type diterpenoids from liverworts having seed dormancy breaking activity and differentiation-inducing activity in mammal cells. </jats:p>