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Article

Nonpolar and Short Side Chain Groups at C-11β of Estradiol Result in Antiestrogens

Jing-xin Zhang,^†^‡ David C. Labaree,^‡ and Richard B. Hochberg*

Department of Obstetrics/Gynecology and Reproductive Sciences, and the Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

J. Med. Chem., 2005, 48 (5), pp 1428–1447

DOI: 10.1021/jm049352x

Publication Date (Web): February 10, 2005

†

Current address: Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016.

‡

Both contributed equally to these studies.

Corresponding author. Phone: (203)785-4001. Fax: (203) 737-4391. E-mail: richard.hochberg@yale.edu.

Abstract

We have previously found that esters of 11β-estradiol carboxylates are transformed from an estrogen into an antiestrogen when the 11β-side chain is increased in length from four to five non-hydrogen atoms (n ≥ 5). To understand the structural requirements for this transformation and obtain metabolically stable analogues that are not susceptible to esterase cleavage, we have synthesized other compounds having an 11β-side chain composed of other functional groups: ketones, amides, ethers, and thiono esters. With the exception of amides, which bind poorly to the estrogen receptor (ER), all of these compounds exhibit antiestrogenic action when the side chain length is n ≥ 5. Ethers (n ≥ 5), studied in more detail, inhibit the action of estradiol with either ERα or ERβ. In rat uteri they are estrogen antagonists/weak agonists and decrease the concentration of cholesterol in blood (an hepatic estrogenic action). Thus, these short chain and nonpolar 11β-analogues of estradiol have tissue specific antiestrogenic/estrogenic actions, characteristics of selective estrogen receptor modulators.

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Published In Issue March 10, 2005
Received August 6, 2004

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Article

Nonpolar and Short Side Chain Groups at C-11β of Estradiol Result in Antiestrogens

Abstract

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Recommend & Share

Related Content

Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure−Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands

Subtle Side-Chain Modifications of the Hop Phytoestrogen 8-Prenylnaringenin Result in Distinct Agonist/Antagonist Activity Profiles for Estrogen Receptors α and β

De Novo Design, Synthesis, and Evaluation of Novel Nonsteroidal Phenanthrene Ligands for the Estrogen Receptor

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