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

BLANCO JAVIER; GIL ROBERTO; BOCCO JOSÉ LUIS; MERAGELMAN TAMARA; GENTI DE RAIMONDI SUSANA; FLURY ALFREDO

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Lugar: Baltimore; Año: 2001 vol. 297 p. 1099 - 1099

ompounds 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 a-methylene-g-lactone group. To synthesize sesquiterpene lactones with greater specificity for aromatase inhibition and lower cytotoxicity, we chemically reduced the a-methylene-g-lactone group in the active aromatase inhibitor 10-epi-8-deoxycumambrin B (compound 1), to obtain the new compound 11bH,13-dihydro-10-epi-8-deoxycumambrin B (compound 2). Reduction of the a-methylene-g-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 5 2 6 0.5 mM versus 7 6 0.5 mM, Ki 5 1.5 mM versus 4.0 mM) and was a more potent type II ligand to the heme iron present in the cytochrome P450arom active site. Compound 2 inhibited aromatase activity in JEG-3 cells in a