Synthesis and Absolute Configuration of the Sesquiterpene Lactone EPD, a Natural Product with Broad Antitumor Cell Activity via a Unique Mechanism of Action

The sesquiterpene lactone eremophila-1(10),11(13)-dien-12,8β-olide (EPD), isolated from leaves of the Calomeria amaranthoides plant, has shown cytotoxic activity on human cancer cell lines, including ovarian cancer-derived cells. To enable further preclinical investigation of EPD as a potential anticancer agent, a chemical synthetic route was developed. NMR and HPLC analysis confirmed that synthetic EPD was identical to natural EPD. The absolute configuration of EPD was established by 3D electron diffraction of a solid precursor. Parallel testing on a panel of more than one hundred human cancer cell lines derived from diverse solid tumors and hematologic malignancies revealed an almost identical profile for synthetic and natural EPD. Furthermore, this profile was unique among 248 anticancer agents that have been profiled on the same panel. These studies merit further investigation of EPD and synthetic analogs for the development of novel anticancer therapies for cancers with high unmet need, including ovarian cancer.