title: Molecular mechanisms of aromatase inhibition by new A, D-ring modified steroids.
abstract: A recent approach for treatment and prevention of estrogen-dependent breast cancer focuses on the inhibition of aromatase, the enzyme that catalyzes the final step of estrogen biosynthesis. Some synthetic steroids, such as formestane and exemestane, resembling the natural enzyme substrate androstenedione, revealed to be potent and useful aromatase inhibitors (AIs) and were approved for the treatment of estrogen-dependent breast cancer in postmenopausal women. Recently, we found that five newly synthesized steroids with chemical features in the A- and D-rings considered important for drug-receptor interaction efficiently inhibit aromatase derived from human placental microsomes. In this work, these steroids showed a similar pattern of anti-aromatase activity in several aromatase-expressing cell lines. 5alpha-androst-3-en-17-one and 3alpha,4alpha-epoxy-5alpha-androstan-17-one were revealed to be the most potent inhibitors. These compounds induced a time-dependent inhibition of aromatase, showing to be irreversible AIs. The specific interactions of these compounds with aromatase active sites were further demonstrated by site-directed mutagenesis studies and evaluated by computer-aided molecular modeling. Both compounds were able to suppress hormone-dependent proliferation of MCF-7aro cells in a dose-dependent manner. These findings are important for the elucidation of a structure-activity relationship on aromatase, which may help in the development of new AIs.
authors: Serviço de Bioquímica, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, 164, 4099-030 Porto, Portugal.
authors: Margarida
authors: M
authors: Cepa
authors: Georgina
authors: G
authors: Correia-da-Silva
authors: Elisiário J
authors: EJ
authors: Tavares da Silva
authors: Fernanda M F
authors: FM
authors: Roleira
authors: Yanyan
authors: Y
authors: Hong
authors: Shiuan
authors: S
authors: Chen
authors: Natércia A
authors: NA
authors: Teixeira
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047072:Aromatase Inhibitors; D050505:Mutant Proteins; D013256:Steroids; D001141:Aromatase