Steroidal inhibitors as chemical probes of the active site of aromatase

Brueggemeier, Robert W.; Moh, Patrick P.; Ebrahimian, Soheila; Darby, Michael V.

doi:10.1016/0960-0760(93)90239-s

Cited by 18 publications

(7 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Very recently, Di Salle et al (30) reported that androst-3,17-dione-4-eno [4,5,6,b,c]pyrole (3) was effective as an aromatase inhibitor. The prevailing explanation for the inhibitory activity of these types of compounds is that the nearby nucleophile attacks at the C-4 position, and the following elimination of a C-4 leaving group results in permanent binding of the inhibitor to the enzyme (26). This hypothesis is based on the assumption that these inhibitors take the same orientation as the substrate in the active site of the enzyme.…”

Section: New Steroidal Inhibitorsmentioning

confidence: 98%

“…Substituents at the C-7α position of the B-ring have provided a number of potent aromatase inhibitors (26,27). Brueggemeir has prepared a wide variety of these and has discovered the presence of a hydrophobic pocket at C-7α that is able to bond covalently to selective steroidal derivatives that are able to correctly extend into this lipophilic region of aromatase.…”

Section: Aromatase Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Design and synthesis of new steroidal inhibitors of estrogen synthase (aromatase)

Parish

Rao

2000

Lipids

View full text Add to dashboard Cite

The estrogen synthase (aromatase) enzyme system is responsible for the biosynthesis of estrogen hormones in human females. Estrogens are vital for normal growth and development, but will promote the growth of certain breast cancers. Approximately 30-50% of breast cancers are considered to be hormone-dependent. Consequently regulation of estrogen biosynthesis has advanced as a potential therapeutic strategy. This has led to the development of active-site inhibitors, which may have potential for the control of breast cancer. We have recently prepared a number of new steroidal inhibitors that have been evaluated as aromatase inhibitors. These include steroidal A/B-ring isoxazoles and a series of A/B-ring pyrazoles with alkyl- and aryl-substituted nitrogen. In addition, we have developed new chemical procedures for the synthesis of 6beta-hydroxy steroids, which could be key intermediates in the preparation of C-19 inhibitors of aromatase activity.

show abstract

Section: New Steroidal Inhibitorsmentioning

confidence: 98%

Section: Aromatase Inhibitionmentioning

confidence: 99%

Design and synthesis of new steroidal inhibitors of estrogen synthase (aromatase)

Parish

Rao

2000

Lipids

View full text Add to dashboard Cite

show abstract

“…The steroidal group includes inhibitors that acts in a competitive manner and certain others by enzyme inhibition or suicide inhibition. 29,30 A mechanism-based inhibitor is an inhibitor that mimics the substrate, which is converted by the enzyme to a reactive intermediate and results in the inactivation of the enzyme. The term "mechanism-based" is used because the inhibitors contains a chemical functionality that is acted upon by the enzyme during the normal catalytic process.…”

Section: Steroidal Inhibitors (Type 1)mentioning

confidence: 99%

Aromatase and Aromatase Inhibitors in Breast Cancer Treatment

Sabale¹,

Sabale²,

Potey³

2018

JCPR

View full text Add to dashboard Cite

Breast cancer is the most common cancer diagnosed in women, remains the second most common causes of death in women in the Western world. With advances in screening, diagnosis and treatment, the death rate for breast cancer patients has declined. Estrogens are responsible for the growth of hormone-dependant breast cancer. Regulation of estrogen biosynthesis is considered as a potential therapeutic strategy for the control of breast cancer. The enzyme aromatase catalyzes conversion of androgens into estrogens in the last step of estrogen biosynthesis. Inhibition of aromatase is adopted as an efficient approach for the prevention and treatment of breast cancer. Many steroidal and non steroidal aromatase inhibitors have been developed and are used clinically for breast cancer therapy. At present, two types of aromatase inhibitors, irreversible steroidal inhibitor and reversible nonsteroidal inhibitors are used in the treatment. Mostly, third-generation aromatase inhibitors are used as potent inhibitors of the aromatase enzyme, which catalyzes the conversion of androgen to estrogen which is the last step in estrogen biosynthesis. This review article aims to highlight about aromatase enzyme, its mechanism and aromatase inhibitors used in the treatment of breast cancer.

show abstract

“…Several evidences have supported the fact that the reactive intermediates result from enzymic oxidation at the C‐19 group of mechanism‐based inhibitors: compounds lacking a C‐19 methyl group did not cause a time‐dependent inhibition; 32 tritium release from [19‐ 3 H]‐19,19‐difluoroandrost‐4‐ene‐3,17‐dione during inactivation of aromatase 33 ; and incubation of androst‐4‐ene‐3,6,17‐trione (AT) with human placental microsome yielded the 19‐hydroxy‐AT and 19‐oxo‐AT 34 . Moreover, experimental results from radioactive inhibitor probe studies demonstrate that a mechanism‐based inhibitor can be covalently bound to aromatase 35 . Mechanism‐based inhibitors provide promising perspectives for drug design because these steroid analogue inhibitors are highly selective and less toxic.…”

Section: Mechanism‐based Inhibitorsmentioning

confidence: 99%

“…34 Moreover, experimental results from radioactive inhibitor probe studies demonstrate that a mechanism-based inhibitor can be covalently bound to aromatase. 35 Mechanism-based inhibitors provide promising perspectives for drug design because these steroid analogue inhibitors are highly selective and less toxic.…”

Section: Mechanism-based Inhibitorsmentioning

confidence: 99%

Aromatase Inhibitors

Hong

Chen

2006

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Aromatase is the enzyme synthesizing estrogens from androgens. In estrogen-dependent breast tumors, estrogens induce the expression of growth factors responsible for cancer cell proliferation. In situ estrogen synthesis by aromatase "is thought to play a key role in the promotion of breast cancer growth. Aromatase inhibitors (AIs) provide new approaches for the prevention and treatment of breast cancer by inhibiting estrogen biosynthesis. Through reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical techniques, aromatase has been found to be expressed in many endocrine tissues and tumors originating from these tissues. Unexpectedly, this enzyme is now known to also be expressed in liver, lung, and colon cancers. Such findings suggest a potential role for endocrine manipulation of these types of cancer using AIs. Three Food and Drug Administration (FDA)-approved AIs, anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin), effectively challenging tamoxifen, have been used as first-line drugs in the treatment of hormone-dependent breast cancer, and possibly other aromatase-expressing cancers. In addition, natural anti-aromatase chemicals, such as flavones and coumarins, have been identified. Efforts to develop new lines of AIs derived from these phytochemicals have been initiated in several laboratories. Finally, significant progress has been made in the understanding of the structure-function relationship of aromatase. Such information has helped the examination of binding characteristics of AIs, the evaluation of reaction mechanism of aromatase, and the explanation of the molecular basis for a low catalytic activity of the natural variant, M364T.

show abstract

Steroidal inhibitors as chemical probes of the active site of aromatase

Cited by 18 publications

References 13 publications

Design and synthesis of new steroidal inhibitors of estrogen synthase (aromatase)

Design and synthesis of new steroidal inhibitors of estrogen synthase (aromatase)

Aromatase and Aromatase Inhibitors in Breast Cancer Treatment

Aromatase Inhibitors

Contact Info

Product

Resources

About