Vol. 297, Issue 3, 1099-1105, June 2001

Aromatase Inhibition by an 11,13-Dihydroderivative of a Sesquiterpene Lactone

Javier G. Blanco, Roberto R. Gil, José L. Bocco, Tamara L. Meragelman, Susana Genti-Raimondi and Alfredo Flury

Departments of Clinical Biochemistry (J.G.B., J.L.B., S.G.-R., A.F) and Organic Chemistry-IMBIV, Consejo Nacional de Investigaciones Científicas y Técnicas (R.R.G., T.L.M.), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina

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 -methylene--lactone group. To synthesize sesquiterpene lactones with greater specificity for aromatase inhibition and lower cytotoxicity, we chemically reduced the -methylene--lactone group in the active aromatase inhibitor 10-epi-8-deoxycumambrin B (compound 1), to obtain the new compound 11H,13-dihydro-10-epi-8-deoxycumambrin B (compound 2). Reduction of the -methylene--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. Compound 2 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, compound 2 inhibited androstenedione-induced uterine hypertrophy in sexually immature mice (41% of uterine weight suppression for compound 2 versus 51% for AG). We conclude that the anti-aromatase activity of sesquiterpene lactones does not depend on the presence of the highly reactive -methylene--lactone group, whereas their cytotoxicity does. These findings may facilitate the development of safer agents for breast cancer therapy.