title: Aromatase inhibition by an 11,13-dihydroderivative of a sesquiterpene lactone.
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 alpha-methylene-gamma-lactone 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 11betaH,13-dihydro-10-epi-8-deoxycumambrin B (compound 2). Reduction of the alpha-methylene-gamma-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 (IC(50) = 2 +/- 0.5 microM versus 7 +/- 0.5 microM, K(i) = 1.5 microM versus 4.0 microM) 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 alpha-methylene-gamma-lactone group, whereas their cytotoxicity does. These findings may facilitate the development of safer agents for breast cancer therapy.
authors.affiliation: Department of Clinical Biochemistry, Consejo Nacional de Investigaciones Científicas y Técnicas, Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina. javier.blanco@stjude.org
authors.forename: J G
authors.initials: JG
authors.lastname: Blanco
authors.forename: R R
authors.initials: RR
authors.lastname: Gil
authors.forename: J L
authors.initials: JL
authors.lastname: Bocco
authors.forename: T L
authors.initials: TL
authors.lastname: Meragelman
authors.forename: S
authors.initials: S
authors.lastname: Genti-Raimondi
authors.forename: A
authors.initials: A
authors.lastname: Flury
mesh_terms: D000616:Aminoglutethimide / Q000494:pharmacology; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002822:Choriocarcinoma / Q000188:drug therapy / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006984:Hypertrophy / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D007783:Lactones / Q000737:chemistry*; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000737:chemistry / Q000201:enzymology; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D014591:Uterine Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000201:enzymology*
chemical_list: C428114:11H,13-dihydro-8-deoxycumambrin; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D007783:Lactones; D012717:Sesquiterpenes; D000616:Aminoglutethimide; D000735:Androstenedione; D001141:Aromatase