A-CD estrogens. I. substituent effects, hormone potency, and receptor subtype selectivity in a new family of flexible estrogenic compounds

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. Obrien, Luke Wan

Research output: Contribution to journalArticlepeer-review

Abstract

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 ERα and ERβ 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 ERα and ERβ, 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-C 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.

Original languageEnglish (US)
Pages (from-to)433-448
Number of pages16
JournalJournal of Medicinal Chemistry
Volume54
Issue number2
DOIs
StatePublished - Jan 27 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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