Molecular mechanisms of aromatase inhibition by new A, D-ring modified steroids

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Margarida Cepa (Author) FFUP; Georgina Correia-da-Silva (Author) FFUP; Elisiário J. Tavares da Silva (Author) Other; Elisário (Author) Other; Fernanda M.F. (Author) Other; Shiuan Che (Author) Other; Natércia A. Teixeira (Author) FFUP

Journal

Title: Biological Chemistry

Vol. 389 No. 9

Pages: 1183-1191

ISSN: 1431-6730

Publisher: Walter De Gruyter

Indexing

ISI Web of Knowledge - 9 Citations

ISI Web of Science

Scopus - 15 Citations

Scientific classification

FOS: Medical and Health sciences > Other medical sciences

CORDIS: Health sciences

Other information

Authenticus ID: P-003-WCH

Resumo (PT): 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. 5a-androst-3-en-17-one and 3a,4a-epoxy-5a-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 sitedirected 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 structureactivity relationship on aromatase, which may help in the development of new AIs. <br> <br> Keywords: aromatase inhibitors; breast cancer; cell lines; computer-assisted protein docking; site-directed mutagenesis studies. <br> <a target="_blank" href="http://web.ebscohost.com/ehost/detail?vid=6&bk=1&hid=6&sid=5f6220ac-40c2-4c00-8965-a314a188bef9%40sessionmgr3&bdata=JnNpdGU9ZWhvc3QtbGl2ZSZzY29wZT1zaXRl#db=a2h&AN=34358780"> Texto integral</a> <br> <br>

Abstract (EN): 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. 5a-androst-3-en-17-one and 3a,4a-epoxy-5a-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 sitedirected 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 structureactivity relationship on aromatase, which may help in the development of new AIs. <br> <br> Keywords: aromatase inhibitors; breast cancer; cell lines; computer-assisted protein docking; site-directed mutagenesis studies. <br> <a target="_blank" href="http://web.ebscohost.com/ehost/detail?vid=6&bk=1&hid=6&sid=5f6220ac-40c2-4c00-8965-a314a188bef9%40sessionmgr3&bdata=JnNpdGU9ZWhvc3QtbGl2ZSZzY29wZT1zaXRl#db=a2h&AN=34358780"> Full text</a> <br> <br>

Language: Portuguese

Type (Professor's evaluation): Scientific