Deconstructing estradiol: Removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists

Mohammud Asim; Mohamed El-Salfiti; Yiming Qian; Christine Choueiri; Samira Salari; James Cheng; Hooman Shadnia; Manpartap Bal; M. A. Christine Pratt; Kathryn E. Carlson; John A. Katzenellenbogen; James S. Wright; Tony Durst

doi:10.1016/j.bmcl.2008.12.080

Deconstructing estradiol: Removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists

Mohammud Asim, Mohamed El-Salfiti, Yiming Qian, Christine Choueiri, Samira Salari, James Cheng, Hooman Shadnia, Manpartap Bal, M. A. Christine Pratt, Kathryn E. Carlson, John A. Katzenellenbogen, James S. Wright, Tony Durst

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Estradiol and related estrogens have been widely used as supplements to relieve menopausal symptoms, but they lead to an increased risk of breast and endometrial cancer. Here we report the synthesis of a new family of compounds where we have removed the B-ring from the steroid ABCD structure, and functionalized the A-ring. These A-CD compounds show a preferential affinity for the estrogen receptor subtype ERβ. Some show binding affinities which are greater than estradiol. The presence of electron-withdrawing substituents on the A-ring should reduce the tendency of these compounds to form carcinogenic metabolites, so they might lead to a safer approach to hormone replacement therapy.

Original language	English (US)
Pages (from-to)	1250-1253
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2008.12.080
State	Published - Feb 15 2009

Keywords

Estradiol
Estrogen receptor selectivity
Hormone replacement therapy
Quinone metabolites
Synthetic hormones

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Online availability

10.1016/j.bmcl.2008.12.080

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Asim, M., El-Salfiti, M., Qian, Y., Choueiri, C., Salari, S., Cheng, J., Shadnia, H., Bal, M., Christine Pratt, M. A., Carlson, K. E., Katzenellenbogen, J. A., Wright, J. S., & Durst, T. (2009). Deconstructing estradiol: Removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists. Bioorganic and Medicinal Chemistry Letters, 19(4), 1250-1253. https://doi.org/10.1016/j.bmcl.2008.12.080

Asim, M, El-Salfiti, M, Qian, Y, Choueiri, C, Salari, S, Cheng, J, Shadnia, H, Bal, M, Christine Pratt, MA, Carlson, KE, Katzenellenbogen, JA, Wright, JS & Durst, T 2009, 'Deconstructing estradiol: Removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 4, pp. 1250-1253. https://doi.org/10.1016/j.bmcl.2008.12.080

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abstract = "Estradiol and related estrogens have been widely used as supplements to relieve menopausal symptoms, but they lead to an increased risk of breast and endometrial cancer. Here we report the synthesis of a new family of compounds where we have removed the B-ring from the steroid ABCD structure, and functionalized the A-ring. These A-CD compounds show a preferential affinity for the estrogen receptor subtype ERβ. Some show binding affinities which are greater than estradiol. The presence of electron-withdrawing substituents on the A-ring should reduce the tendency of these compounds to form carcinogenic metabolites, so they might lead to a safer approach to hormone replacement therapy.",

keywords = "Estradiol, Estrogen receptor selectivity, Hormone replacement therapy, Quinone metabolites, Synthetic hormones",

author = "Mohammud Asim and Mohamed El-Salfiti and Yiming Qian and Christine Choueiri and Samira Salari and James Cheng and Hooman Shadnia and Manpartap Bal and {Christine Pratt}, {M. A.} and Carlson, {Kathryn E.} and Katzenellenbogen, {John A.} and Wright, {James S.} and Tony Durst",

note = "Funding Information: The authors thank the Canadian Foundation for Breast Cancer, Ontario Chapter, and NSERC Canada for support of this work and the National Institutes of Health (PHS 5R37DK15556) for support to J.A.K. ",

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AU - Qian, Yiming

AU - Choueiri, Christine

AU - Salari, Samira

AU - Cheng, James

AU - Shadnia, Hooman

AU - Bal, Manpartap

AU - Christine Pratt, M. A.

AU - Carlson, Kathryn E.

AU - Katzenellenbogen, John A.

AU - Wright, James S.

AU - Durst, Tony

N1 - Funding Information: The authors thank the Canadian Foundation for Breast Cancer, Ontario Chapter, and NSERC Canada for support of this work and the National Institutes of Health (PHS 5R37DK15556) for support to J.A.K.

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KW - Quinone metabolites

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Deconstructing estradiol: Removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists

Abstract

Keywords

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