Aromatase inhibition by an 11,13-dihydroderivative of a sesquiterpene lactone

Compounds that inhibit aromatase activity are used for the treatment of bre ast cancer. A group of sesquiterpene lactones inhibit aromatase activity an d also exert cytotoxicity through their reactive alpha -methylene-gamma -la ctone group. To synthesize sesquiterpene lactones with greater specificity for aromatase inhibition and lower cytotoxicity, we chemically reduced the alpha -methylene-gamma -lactone group in the active aromatase inhibitor 10- epi-8-deoxycumambrin B (compound 1), to obtain the new compound 11 betaH,13 -dihydro-10-epi-8-deoxycumambrin B (compound 2). Reduction of the alpha -me thylene-gamma -lactone group abrogated the cytotoxic activity of compound 1 against the JEG-3, HeLa, and COS-7 cell lines. Compound 2 had higher aroma tase inhibitory activity than compound 1 (IC50 = 2 +/- 0.5 muM versus 7 +/- 0.5 muM, K-i = 1.5 muM versus 4.0 muM) and was a more potent type II ligan d to the heme iron present in the cytochrome P450(arom) active site. Compou nd 2 inhibited aromatase activity in JEG-3 cells in a comparable manner to the inhibitor aminoglutethimide (AG) used clinicalldditionally, 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 alpha -methylene-gamma - lactone group, whereas their cytotoxicity does. These findings may facilita te the development of safer agents for breast cancer therapy.