Natural daucane sesquiterpenes with antiproliferative and proapoptotic activity against human tumor cells

Plants of the genera Ferula and Ferulago are known for their complex content in bioactive secondary metabolites such as coumarins, phenylpropanoids, and sesquiterpenes. We used the ground parts of Ferula communis subsp. communis, Ferula glauca subsp. glauca and Ferulago campestris as natural sources for the isolation of four coumarins (CU-1 to CU-4), two phenylpropanoids (PE-1 and PE-2), one polyacetylene (PA-1) and 16 daucane esters (DE-1 to DE-16). The cytotoxic activity of the isolated compounds was evaluated against a panel of seven human tumor cell lines. Fourteen of the daucane derivatives showed antiproliferative activity at least against one of the human tumor cell lines tested, four compounds (DE-5, DE-8, DE-11, and DE-16) were active against all the tested cell lines. Among them DE-11 was the most cytotoxic compound against HeLa (4.4 +/- 0.7 mu M), A549 (2.8 +/- 1.4 mu M), HL-60 (2.6 +/- 0.4 mu M), K562 (26.5 +/- 6.0 mu M) RS 4:11(1.7 +/- 0.3 mu M) and SEM (2.4 +/- 0.1 mu M) cell lines, while DE-8 was the most active against Jurkat (3.3 +/- 0.8 mu M). Preliminary structure-activity relationship suggests that the most active compounds in the daucane series present the trans fusion of the penta- and hepta-atomic cycles, and lipophylic ester groups linked to position 6. Isomeric derivatives such as DE-8 and DE-9 or DE-3, DE-4, and DE-5 exhibited significant differences in their IC(50) supporting that the p orientation for the ester group in the position 2 enhances the cytotoxic activity. Furthermore, the pro-apoptotic effect of the most active compounds evaluated in Jurkat cell line showed that these compounds are able to induce apoptosis in a time and concentration-dependent manner. Our findings suggest the potential role of daucane derivatives as models for the development of proapoptotic compounds.