Cyclopentenediones, inhibitors of farnesyl protein transferase and anti-tumor compounds, isolated from the fruit of Lindera erythrocarpa Makino

Four cyclopentenediones, farnesyl protein transferase inhibitors, and anti-tumor compounds were isolated from the methanolic extract of the fruits of Lindera erythrocarpa Makino (Lauraceae). The structure of the compounds was determined by spectral data including NMR and mass spectrometry, and cyclopentenediones such as methyllinderone (1), methyllucidone (2), lucidone (3), and linderone (4) were identified by comparing their reported spectral data with that of the literature values. Compounds 1-4 inhibited farnesyl protein transferase with IC50 value of 55.3+/-4.1, 42+/-1.9, 103+/-5.1, and 40+/-3.5 microM, respectively. Isolated compounds also inhibited the growth of various human cancer cell lines in a dose-dependent manner. Especially, Compounds 1 and 2 selectively inhibited the growth of H-ras-transformed rat-2 cell lines in comparison with normal rat-2 cells with a GI50 value of 0.3 and 0.85 microM, respectively. Methyllucidone strongly inhibited the growth of human cancer cells and colon tumor xenografted in nude mice. The anti-tumor effects of the compound were further confirmed with caspase-3 activation and degradation of PARP. The results suggest that methyllucidone can be a potential anti-cancer agent against H-ras-transformed tumor and will also be a good lead molecule for the development of anti-tumor drug.