TY - JOUR
T1 - A-CD estrogens. I. substituent effects, hormone potency, and receptor subtype selectivity in a new family of flexible estrogenic compounds
AU - Wright, James S.
AU - Shadnia, Hooman
AU - Anderson, James M.
AU - Durst, Tony
AU - Asim, Muhammad
AU - El-Salfiti, Mohamed
AU - Choueiri, Christine
AU - Pratt, M. A.Christine
AU - Ruddy, Samantha C.
AU - Lau, Rosanna
AU - Carlson, Kathryn E.
AU - Katzenellenbogen, John A.
AU - Obrien, Peter J.
AU - Wan, Luke
PY - 2011/1/27
Y1 - 2011/1/27
N2 - 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.
AB - 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.
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U2 - 10.1021/jm100513m
DO - 10.1021/jm100513m
M3 - Article
C2 - 21190382
AN - SCOPUS:78751678808
SN - 0022-2623
VL - 54
SP - 433
EP - 448
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -