title: Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens.
abstract: High levels of endogenous estrogens are associated with increased risks of breast cancer. Estrogen levels are mainly increased by the activity of the aromatase enzyme and reduced by oxidative/conjugative metabolic pathways. In this paper, we demonstrate for the first time that catechol estrogen metabolites are potent aromatase inhibitors, thus establishing a link between aromatase activity and the processes involved in estrogen metabolism. In particular, the anti-aromatase activity of a set of natural hydroxyl and methoxyl estrogen metabolites was investigated using biochemical methods and subsequently compared with the anti-aromatase potency of estradiol and two reference aromatase inhibitors. Catechol estrogens proved to be strong inhibitors with an anti-aromatase potency two orders of magnitude higher than estradiol. A competitive inhibition mechanism was found for the most potent molecule, 2-hydroxyestradiol (2-OHE(2)) and a rational model identifying the interaction determinants of the metabolites with the enzyme is proposed based on ab initio quantum-mechanical calculations. A strong relationship between activity and electrostatic properties was found for catechol estrogens. Moreover, our results suggest that natural catechol estrogens may be involved in the control mechanisms of estrogen production.
authors: Centro de Estudos Farmacêuticos, Lab. Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, 3000-295 Coimbra, Portugal.
authors: Marco A C
authors: MA
authors: Neves
authors: Teresa C P
authors: TC
authors: Dinis
authors: Giorgio
authors: G
authors: Colombo
authors: M
authors: M
authors: Luisa Sá E Melo
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis / Q000187:drug effects; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology; D002393:Estrogens, Catechol / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure
chemical_list: D047072:Aromatase Inhibitors; D004967:Estrogens; D002393:Estrogens, Catechol; D004958:Estradiol; D001141:Aromatase