Estrogens Containing Alkylating Substituents: The Synthesis and Estrogen Receptor Interactions of Estradiol and Hexestrol Affinity Labels
Mcgorrin, Robert Joseph, Jr.
This item is only available for download by members of the University of Illinois community. Students, faculty, and staff at the U of I may log in with your NetID and password to view the item. If you are trying to access an Illinois-restricted dissertation or thesis, you can request a copy through your library's Inter-Library Loan office or purchase a copy directly from ProQuest.
Permalink
https://hdl.handle.net/2142/67247
Description
Title
Estrogens Containing Alkylating Substituents: The Synthesis and Estrogen Receptor Interactions of Estradiol and Hexestrol Affinity Labels
Author(s)
Mcgorrin, Robert Joseph, Jr.
Issue Date
1980
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
A series of chemically-reactive derivatives of estradiol and the non-steroidal estrogen hexestrol have been synthesized as potential affinity labels for the uterine estrogen receptor, or as cytotoxic agents with selective activity against receptor-containing cells. These compounds are hexestrol ethers with haloketone, halohydrin, or epoxide functions; 4-substituted deoxyhexestrols with nitro, azide, sulfonyl fluoride, or sulfonyl azide groups; and estradiol and hexestrol analogs incorporating benzyl halide functions ortho to the phenol or the corresponding methyl ether. The alkylating activity of the electrophilic derivatives was measured using the colorimetric reagent 4-(p-nitrobenzyl)pyridine, and the bromo derivatives were found to be consistently more reactive than the chloro ones. Their reversible binding to the lamb uterine estrogen receptor was measured by competitive binding assays, and their irreversible reaction with receptor was measured by exchange assays that determine the rate and extent of receptor inactivation. In general, etherification of hexestrol or substitution of deoxyhexestrol and estradiol produces compounds with relatively modest affinity for the estrogen receptor (0.3-10% that of estradiol). Most of the electrophilic derivatives are effective and rapid inactivators of receptor (24-44% inactivation within 0.5-5 hr at 25(DEGREES)C). Of the photosensitive derivatives, 4-azidodeoxyhexestrol appears to be the most efficient receptor inactivator (49%). The high estrogen receptor activity and the lack of interference by cellular nucleophiles suggests that these compounds may be useful as affinity labeling agents, or as selective cytotoxic agents in intact systems.
Use this login method if you
don't
have an
@illinois.edu
email address.
(Oops, I do have one)
IDEALS migrated to a new platform on June 23, 2022. If you created
your account prior to this date, you will have to reset your password
using the forgot-password link below.
