Side Chain Functionalized Hexestrols and Norhexestrols as Probes for the Estrogen Receptor
Landvatter, Scott White
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Permalink
https://hdl.handle.net/2142/70189
Description
Title
Side Chain Functionalized Hexestrols and Norhexestrols as Probes for the Estrogen Receptor
Author(s)
Landvatter, Scott White
Issue Date
1982
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
Derivatives of non-steroidal estrogens, such as meso-hexestrol, can interact with the estrogen receptor in four possible binding modes--two per enantiomer. Several side chain functionalized hexestrol and norhexestrol derivatives have been synthesized and resolved into pure enantiomers. Binding studies with lamb uterine estrogen receptor indicate that there is no appreciable difference in binding between enantiomers in the hexestrol series while enantiomers in the norhexestrol series do show significant differences in binding. It is concluded that the norhexestrols prefer one of the four possible binding modes while the hexestrols can adopt two of the four modes equally.
Differential binding is also observed between pairs of hexestrol diastereomers functionalized at the secondary position of the side chain (bromide and alcohol). In each case the high binding diastereomer has the (2S*, 3R*, 4S*) configuration.
Several other side chain functionalized hexestrols and norhexestrols have been prepared; these include alcohol, amide, diazoketone, ester, ketone, fluoro, bromo, iodo, and saturated hydrocarbon derivatives. Analysis of the binding affinity of these compounds reveals trends which can be related to steric size, hydrophobicity, and hydrogen bonding ability of the side chain substituent. Comparison of binding affinities between the two series of compounds indicates that, in general, the norhexestrols bind with greater affinity to the estrogen receptor.
Two gamma-emitting estrogen analogs, erythro-1-{('125)I}-Iodo-2,3-bis(4-hydroxyphenyl)pentane and erythro-1-{('77)Br}-Bromo-2,3-bis(4-hydroxyphenyl)pentane, have also been prepared. In immature female rats, both of these halonorhexestrols demonstrate preferential uptake by uterus that could be blocked selectively be coadministration of a large dose of unlabeled estradiol. Stability studies in vitro and in vivo indicate that both iodo and bromonorhexestrol are quite labile, and this lability compromises the selectivity of their uptake by estrogen sensitive target tissues in vivo. p-Hydroxyphenylethyl halides are known to be unusually prone to base-catalyzed solvolysis, via cyclization of the phenolate to a spirocyclohexadienone intermediate. This unusual solvolytic mechanism may contribute to the lability of these halonorhexestrols in vivo.
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