Design, synthesis, and biochemical evaluation of three types of hexestrol-based probes for estrogen receptor: Fluorine-18 radiopharmaceuticals, bivalent ligands and diazirine photoaffinity reagents
Bergmann, Kathryn Ellen
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https://hdl.handle.net/2142/21617
Description
Title
Design, synthesis, and biochemical evaluation of three types of hexestrol-based probes for estrogen receptor: Fluorine-18 radiopharmaceuticals, bivalent ligands and diazirine photoaffinity reagents
Author(s)
Bergmann, Kathryn Ellen
Issue Date
1993
Doctoral Committee Chair(s)
Katzenellenbogen, John A.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Language
eng
Abstract
The estrogen receptor (ER) has become a major focus of biological and clinical investigation in diagnostic and therapeutic drug design for human breast carcinoma. Molecular probes, such as fluorine-18 radiopharmaceuticals, bivalent ligands, and affinity labels, provide information toward a better understanding of ER localization, structure, and function. We have prepared two fluorinated analogs of 2-oxohexestrol as potential diagnostic imaging agents for ER-responsive human breast tumors. These ligands were prepared in fluorine-18 labeled form with high specific activity (328-609 Ci/mmol) by fluoride ion (n-Bu$\sb4$N$\sp{18}$F) displacement of a mesylate and triflate precursor. Preliminary studies on the unlabeled compounds showed them to have low lipophilicity and good receptor binding affinity; these results were reflected in the tissue distribution studies of the radiolabeled compounds with moderate selective uptake in target tissues (uterus, ovaries) and substantial receptor-mediated uptake in secondary tissues (thymus, muscle, kidney, fat).
Bivalent ligands for ER consisting of two hexestrol moieties linked with variable length spacer chains have been prepared as molecular probes for the study of receptor dimerization and of how dimerization mediates the actions of estrogens and antiestrogens. Four of the shorter spacer length dimers ($\le$4 atoms) were found to have moderate affinity for ER, and four of the erythro-erythro bivalent ligands with spacer lengths of 4-8 atoms exhibited biphasic displacement of estradiol in a receptor binding assay. The longer spacer dimers retained unfavorable lipophilicity properties. The two erythro-erythro ester linked dimers of 4 and 8 atom spacers suppressed estradiol induction in transcription assays, while the corresponding monomeric compounds and erythro-threo isomers were partial/mixed antagonists or full agonists signifying differential interaction of the ligand with receptor and/or of the receptor with the transcriptional apparatus.
Affinity labels are important tools in studying ligand-receptor contact points within the receptor binding domain. A hexestrol derivative functionalized with a photoactivatable diazirine group has been prepared in unlabeled and high specific activity (32 Ci/mmol) radiolabeled form. The hexestrol diazirine was found to have high affinity for ER and demonstrated highly efficient and selective photocovalent attachment to ER.
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