Diterpenoids from Cephalotaxus fortunei var. alpina and their cytotoxic activity

Cephafortunoids A-D (1-4), four new compounds, together with ten known ones (5-14), were isolated from the branches and leaves of Cephalotaxus fortunei var. alpina. 1 and 2 represent the first examples of Cephalotaxus troponoid diterpenoids featured an intact C₂₀ skeleton with CH₃-17 migrating to C-15 and C-13 respectively. 3 and 4 are novel cephalotane-type diterpenoids with an epoxy ring between C-12 and C-13. The structures of isolated compounds were established by extensive spectroscopic methods, electronic circular dichroism (ECD) calculations, and comparison with reported data. In in vitro bioassays, all isolated compounds were evaluated for their cytotoxic activities against human promyelocytic leukemia cells (HL-60), human acute monocytic leukemia cells (THP-1), human breast cancer cells (MDA-MB-231), and human prostate cancer cells (PC-3). 5-9 exhibited prominent cytotoxicity against HL-60 and THP-1 with GI₅₀ values of 0.27-5.48 and 0.48-7.54 μM, respectively. 5-8 showed evident cytotoxicity against MDA-MB-231 and PC-3 with IC₅₀ values of 1.96-10.66 and 2.72-13.99 μM, severally. 6 with an IC₅₀ value of 2.72 ± 0.35 μM displayed stronger cytotoxicity against PC-3 than the positive control etoposide. The structure-activity relationship of these compounds and plausible biogenetic pathways for 1-4 were discussed.