Design, Synthesis and Biological Properties of Fluorinated Estrogens, Progestins and Androgens, Potential Imaging Agents for Receptor-Positive Mammary and Prostate Tumors (fluorine-18)
Brandes, Stephanie Jean
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https://hdl.handle.net/2142/70339
Description
Title
Design, Synthesis and Biological Properties of Fluorinated Estrogens, Progestins and Androgens, Potential Imaging Agents for Receptor-Positive Mammary and Prostate Tumors (fluorine-18)
Author(s)
Brandes, Stephanie Jean
Issue Date
1986
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
Abstract
Several estrogens fluorinated at the 17(alpha)- and 16(alpha)-positions were synthesized in the development of a potential fluorine-18 radiolabel useful as a means of quantifying estrogen receptor in receptor-positive mammary tumors. The affinities of the compounds for estrogen receptor were measured using competitive radiometric binding assays and 17(alpha)-fluoromethyl estradiol (17) and 17(alpha)-fluoropropynyl estradiol (18) found to bind to this receptor system with affinities 52% and 84% that of estradiol respectively. A method for rapidly and efficiently synthesizing 17(alpha)-fluoromethyl estradiol by fluoride ion cleavage of the corresponding C-17 spiro cyclic sulfate was developed by modifying the C-3 protecting group of the sulfate precursor and reaction time, temperature and solvent.
In studies directed towards the development of radiolabelled probes for progesterone receptor in mammary tumors and androgen receptor in prostate tumors, a series of fluorinated progestins and androgens were prepared. Fluoride was introduced into the 6(alpha)-, 11(beta)- and 16(alpha)-positions of the molecules by bromofluorination of an appropriate alkene, and into the 17(alpha)-position by substitution of a methansulfonate using tetrabutylammonium fluoride or fluoride ion cleavage of a spiro epoxide or cyclic sulfate. The affinities of the compounds for progesterone- and androgen receptors were determined, and several of the steroids were found to exhibit the good affinities and selectivities for their respective receptors predicted on the basis of general substituent trends. Fluoropropynyl nortestosterone 119 bound with the highest affinity to progesterone receptor (66% that of progesterone), and 11(beta)-fluoro-19-nordihydrotestosterone (90) maintained the highest affinity for androgen receptor (130% that of dihydrotestosterone) of the compounds tested. Nortestosterone 119 can be rapidly prepared in good yield by the fluoride displacement of the corresponding methanesulfonate 131. Similarly, the synthesis of fluorodihydrotestosterone 76, a model for nordihydrotestosterone 90, was modified in order that fluoride can be introduced quickly and efficiently. The two-step reaction sequence involves a bromofluorination followed by reductive debromination.
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