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Title:Synthesis and biological evaluation of 11beta-substituted and 7alpha-substituted estradiol analogs for the study of estrogen responsive breast tumors
Author(s):French, Andrew Nichols
Doctoral Committee Chair(s):Katzenellenbogen, John A.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Abstract:We have synthesized six estrogens substituted at the 11$\beta$-position with a fluoroalkyl or fluoroalkoxy substituent. These compounds bind to the estrogen receptor with high affinity, with the fluoroalkyl analogs being somewhat better binders than the fluoroalkoxy ones. All of these fluorine-substituted estrogens were prepared in fluorine-18 labeled form, with high radiochemical purity and at effective specific activities (415-1362 Ci/mmol), adequate for biodistribution studies. In immature female rats, five of the six fluoroestrogens showed selective uptake by the uterus, with uterine uptake as a percent of the injected dose per gram being 4-9% at 1 h, and uterus to blood or muscle ratios being 10-40. Selective uterine uptake was eliminated by co-administration of a blocking dose of unlabeled estradiol. The only compound that did not show selective uterine uptake was 11$\beta$-fluoropropoxyl estradiol; its rapid metabolism may account for its lack of specific uptake. The level of bone activity, an index of metabolic defluorination, shows that the defluorination rates of these six estrogens are a complex function of structure and functionality. Least prone to defluorination is 11$\beta$-(2-fluoroethoxy)estradiol and most prone is 11$\beta$-(2-fluoroethyl)estradiol. The extent of defluorination of the remaining compounds shows weak evidence for the protective effect of a heteroatom substituted beta to the site of metabolism (the CH bonds on the fluorine-bearing carbon atom).
In an effort to assist in the preparation of new ligands for the study of the estrogen receptor (ER), we have developed a new synthesis of 7$\alpha$-substituted estradiols. The key step in the synthesis involves a copper-catalyzed, $\alpha$-selective, 1,6-conjugate addition to a suitably protected 6-dehydrotestosterone derivative. Reductive aromatization of the resulting 7$\alpha$-pentenyl androgen gave the 7$\alpha$-pentenylestradiol in good yields. While previously this reaction was done in the 19-nortestosterone series, the $\alpha$-stereoselectivity of this addition in the testosterone series is improved to a large extent by the presence of the C19 methyl group, which shields the beta face from attack. A key intermediate was functionalized further, by substitution with fluorine-18 to provide a potential PET imaging agent, and by conjugation with a BODIPY$\sp{\rm TM}$ fluorophore to make a fluorescent probe for ER. The synthesis and biological evaluation of these analogs, as well as a discussion of the synthesis are presented. The binding affinity, tissue distribution and metabolism of these 11$\beta$-fluoroalkyl-, fluoroalkoxy-, and 7$\alpha$-pentyl-substituted estrogens further our understanding of the behavior of differentially substituted estrogens as potential imaging agents and probes for estrogen receptor-positive breast cancer.
Issue Date:1992
Rights Information:Copyright 1992 French, Andrew Nichols
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9236463
OCLC Identifier:(UMI)AAI9236463

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