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

Biological Chemistry
Margarida M D S CepaNatércia A A Teixeira

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 t...Continue Reading

References

Dec 1, 1992·The Journal of Steroid Biochemistry and Molecular Biology·N KadohamaY Osawa
Nov 20, 1990·The Journal of Steroid Biochemistry and Molecular Biology·W R Miller, J S O'Neill
Nov 20, 1990·The Journal of Steroid Biochemistry and Molecular Biology·A M BrodieR C Coombes
Dec 20, 1990·The Journal of Steroid Biochemistry and Molecular Biology·S Green
Apr 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·Y BerthoisB S Katzenellenbogen
Jan 1, 1986·Journal of Steroid Biochemistry·M E LippmanS Swain
Mar 1, 1974·The Journal of Clinical Endocrinology and Metabolism·D L HemsellP C MacDonald
Aug 1, 1981·The Journal of Clinical Endocrinology and Metabolism·G E AckermanE R Simpson
Mar 25, 2000·Endocrine-related Cancer·R J Santen, H A Harvey
Nov 15, 2000·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·J M NabholtzM von Euler
Feb 13, 2001·European Journal of Biochemistry·Y C KaoS Chen
Feb 19, 2002·The Journal of Steroid Biochemistry and Molecular Biology·W R MillerT J Anderson
Mar 15, 2003·Nature Reviews. Cancer·Simak Ali, R Charles Coombes
Jul 31, 2003·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·J M NabholtzB Thürlimann
Nov 19, 2003·The Journal of Steroid Biochemistry and Molecular Biology·E R Simpson
Oct 6, 2006·Expert Opinion on Pharmacotherapy·Robert W Brueggemeier

❮ Previous
Next ❯

Citations

Jul 12, 2013·Apoptosis : an International Journal on Programmed Cell Death·Cristina AmaralNatércia Teixeira
Aug 23, 2012·PloS One·Cristina AmaralNatércia Teixeira
Jan 16, 2013·The Journal of Steroid Biochemistry and Molecular Biology·Cristina AmaralNatércia Teixeira
May 20, 2009·Frontiers in Neuroendocrinology·Colin J SaldanhaBradley J Walters
May 28, 2020·International Journal of Molecular Sciences·Bagora BayalaJean-Marc A Lobaccaro
Jun 12, 2020·European Journal of Medicinal Chemistry·Ana R GomesFernanda M F Roleira

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.