A-CD Estrogens. I. Substituent Effects, Hormone Potency, and Receptor Subtype Selectivity in a New Family of Flexible Estrogenic Compounds

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• 作者：James S. Wright ; Hooman Shadnia ; James M. Anderson ; Tony Durst ; Muhammad Asim ; Mohamed El-Salfiti ; Christine Choueiri ; M. A. Christine Pratt ; Samantha C. Ruddy ; Rosanna Lau ; Kathryn E. Carlson ; John A. Katzenellenbogen ; Peter J. O鈥橞rien ; Luke Wan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 27, 2011
• 年：2011
• 卷：54
• 期：2
• 页码：433-448
• 全文大小：1212K
• 年卷期：v.54,no.2(January 27, 2011)
• ISSN：1520-4804

文摘

Long-term use of estrogen supplements by women leads to an increased risk of breast and uterine cancers. Possible mechanisms include metabolism of estradiol and compounds related to tumor-initiating quinones, and ligand-induced activation of the estrogen receptors ER伪 and ER尾 which can cause cancer cell proliferation, depending on the ratio of receptors present. One therapeutic goal would be to create a spectrum of compounds of variable potency for ER伪 and ER尾, which are resistant to quinone formation, and to determine an optimum point in this spectrum. We describe the synthesis, modeling, binding affinities, hormone potency, and a measure of quinone formation for a new family of A-CD estrogens, where the A鈭扖 bond is formed by ring coupling. Some substituents on the A-ring increase hormone potency, and one compound is much less quinone-forming than estradiol. These compounds span a wide range of receptor subtype selectivities and may be useful in hormone replacement therapy.