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Title:The synthesis and evaluation of estrogenic probes for in vitro and in vivo studies
Author(s):Scribner, Andrew William
Doctoral Committee Chair(s):Katzenellenbogen, John A.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Health Sciences, Oncology
Abstract:Our research group has for over twenty years had a strong interest in developing molecular probes for steroid hormone receptors, and in particular, the estrogen receptor (ER), in order to further elucidate its structure and function, and to aid in the clinical evaluation and treatment of patients suffering from breast cancer. This thesis focuses on the preparation and evaluation of estrogenic probes for two types of analyses to achieve this goal: in vitro studies and in vivo studies.
For in vitro studies, we have prepared three fluorescent affinity labels (80-82) which are analogs of the antiestrogen nafoxidine, each possessing both a pyridine ring to enhance fluorescence emission, and an aziridine ring to covalently bind to ER. All three aziridines were prepared in 14 to 15 steps from monocyclic precursors, and each were found to exhibit modest to high relative binding affinity (RBA, estradiol = 100%) for ER (27-62%), as did various intermediates and related analogs prepared. Extensive spectroscopic studies were then performed on four benzyl ether protected intermediates (117-120) resulting from the photocyclization of their stilbazole precursors.
For in vivo studies, we have prepared two fluorine-18 labeled isomeric estrogens 121 and 122) which are analogs of the potent estrogen doisynolic acid. Each isomer was labeled at the 16-17 position due to the relative ease in incorporating fluoride at this position. Each differed only in stereochemistry at the 14-position, as doisynolic acid possessing the unnatural cis, or 14$\beta$ configuration has been found to be even more potent in vivo than its isomer with the natural trans, or 14$\alpha$ stereochemistry. Both isomers were prepared in 10-13 steps from estrone. First, the fluorine-19 labeled isomers (145 and 146) were prepared, and found to have low RBAs for ER (1.0-2.0%). Both radiolabeled isomers were then prepared and injected into immature female rats for biodistribution and metabolism studies. The 14$\alpha$-isomer (121) showed extremely weak uterine uptake at 1 hour (0.5% injected dose per gram), and apparently underwent extensive defluorination. The 14$\beta$-isomer (122), on the other hand, showed modest uterine uptake at 1 hour (3.4-4.7% injected dose per gram), which increased over time (up to 8.9% injected dose per gram at 5 hours), with considerably less defluorination and lower clearance from all tissues. Fluoride 121 showed modest metabolism to a more polar metabolite, whereas fluoride 122 showed no detectable metabolism at all.
Lastly, we have prepared compounds which bear structural resemblance to dihalosubstituted analogs of the synthetic estrogen hexestrol. The two targets prepared, bishomohexestrol (162) and dimethylhexestrol (163), each displayed high RBA for ER, (38% and 120%, respectively), and were found through MacroModel to have estimated volumes quite comparable to the dihalosubstituted hexestrol analogs concurrently being synthesized. All of these compounds were prepared to aid in the X-ray crystallographic elucidation of ER by multiple isomorphous replacement. (Abstract shortened by UMI.)
Issue Date:1996
Rights Information:Copyright 1996 Scribner, Andrew William
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9712432
OCLC Identifier:(UMI)AAI9712432

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