Conjugated Estrogen Receptor Probes: An Evaluation of Fluorophores, Photolabile Groups, Estrogenic Ligands, and the Nature of the Attaching Chain
Fevig, Thomas Lee
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https://hdl.handle.net/2142/70344
Description
Title
Conjugated Estrogen Receptor Probes: An Evaluation of Fluorophores, Photolabile Groups, Estrogenic Ligands, and the Nature of the Attaching Chain
Author(s)
Fevig, Thomas Lee
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
A good correlation exists between the level of estrogen receptor in breast tumors, and their responsiveness to hormone therapy. However, the correlation is not perfect; about 40% of women with measurable tumor receptor levels do not respond to hormone treatment. The work described herein was undertaken in order to improve the predictability of hormone responsiveness.
This research focusses on the synthesis of estrogen-fluorophore conjugates with which to perform single cell assays of estrogen receptor. If successful, this would reveal the cellular hetero- or homogeneity of receptor content of tumors, possibly leading to an enhanced predictability of hormone responsiveness. Secondarily, the structure and mechanism of action of estrogen receptor are being studied through the preparation of model compounds and photoaffinity labels.
Hexestrol derivatives substituted ortho to the hydroxyl group were prepared by an allylation/Claisen rearrangement sequence, followed by functionalization of the o-allyl group. In addition to several model compounds, three fluorescent and two photolabile derivatives were synthesized. The fluorescent conjugates have affinities for the receptor ranging from 1 to 7% that of the reference compound, estradiol. An extensive examination of the fluorophores used revealed the NBD (nitrobenzoxadiazole) group to be a suitable fluorophore. The photolabile derivatives have low affinity for the receptor (<2%), however, one of them showed a specific inactivation efficiency of ca. 25%.
An efficient, highly stereoselective route to 16(alpha)-substituted estradiol derivatives has been devised. The pathway involves alkylation of an estrone enolate with functionalized, activated electrophiles, followed by side chain manipulation and reduction of the 17-ketone. The fluorescent compounds prepared by this route have low affinity (<1%) for receptor. However, several of the model compounds, and one photolabile one, bind well, and suggest that unsaturation in the side chain is an important factor to consider for future studies.
One potential synthesis of 7(alpha)-substituted estradiol derivatives, involving alkylation of a 6-oxo enolate, was deemed unfeasible when the alkylation reaction failed with all electrophiles tried save methyl iodide. An improved synthesis, based on a published procedure, is proposed.
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