Abstract

Compounds that inhibit aromatase activity are used for the treatment of breast cancer. A group of sesquiterpene lactones inhibit aromatase activity and also exert cytotoxicity through their reactive α-methylene-γ-lactone group. To synthesize sesquiterpene lactones with greater specificity for aromatase inhibition and lower cytotoxicity, we chemically reduced the α-methylene-γ-lactone group in the active aromatase inhibitor 10-epi-8-deoxycumambrin B (compound1), to obtain the new compound 11βH,13-dihydro-10-epi-8-deoxycumambrin B (compound 2). Reduction of the α-methylene-γ-lactone group abrogated the cytotoxic activity of compound 1 against the JEG-3, HeLa, and COS-7 cell lines. Compound 2 had higher aromatase inhibitory activity than compound 1(IC₅₀ = 2 ± 0.5 μM versus 7 ± 0.5 μM, K_i = 1.5 μM versus 4.0 μM) and was a more potent type II ligand to the heme iron present in the cytochrome P450_arom active site. Compound2 inhibited aromatase activity in JEG-3 cells in a comparable manner to the inhibitor aminoglutethimide (AG) used clinically for the treatment of breast cancer. Additionally, compound2 inhibited androstenedione-induced uterine hypertrophy in sexually immature mice (41% of uterine weight suppression for compound2 versus 51% for AG). We conclude that the anti-aromatase activity of sesquiterpene lactones does not depend on the presence of the highly reactive α-methylene-γ-lactone group, whereas their cytotoxicity does. These findings may facilitate the development of safer agents for breast cancer therapy.