Synthesis and biological evaluation of 11beta-substituted and 7alpha-substituted estradiol analogs for the study of estrogen responsive breast tumors

We have synthesized six estrogens substituted at the 11β-position with a fluoroalkyl or fluoroalkoxy substituent. These compounds bind to the estrogen receptor with high affinity, with the fluoroalkyl analogs being somewhat better binders than the fluoroalkoxy ones. All of these fluorine-substituted estrogens were prepared in fluorine-18 labeled form, with high radiochemical purity and at effective specific activities (415-1362 Ci/mmol), adequate for biodistribution studies. In immature female rats, five of the six fluoroestrogens showed selective uptake by the uterus, with uterine uptake as a percent of the injected dose per gram being 4-9% at 1 h, and uterus to blood or muscle ratios being 10-40. Selective uterine uptake was eliminated by co-administration of a blocking dose of unlabeled estradiol. The only compound that did not show selective uterine uptake was 11β-fluoropropoxyl estradiol; its rapid metabolism may account for its lack of specific uptake. The level of bone activity, an index of metabolic defluorination, shows that the defluorination rates of these six estrogens are a complex function of structure and functionality. Least prone to defluorination is 11β-(2-fluoroethoxy)estradiol and most prone is 11β-(2-fluoroethyl)estradiol. The extent of defluorination of the remaining compounds shows weak evidence for the protective effect of a heteroatom substituted beta to the site of metabolism (the CH bonds on the fluorine-bearing carbon atom).

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• French, Andrew Nichols

Contributors dc:contributor

• Katzenellenbogen, John A.

• Chemistry, Organic

Statement dc:rights

• Copyright 1992 French, Andrew Nichols

Language dc:language

eng

Identifier

AAI9236463
(UMI)AAI9236463

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/21152