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| - Synthesis and Biological Evaluation of 4-(Hydroxyalkyl)estradiols and RelatedCompounds
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| - A series of synthetic estrogens containing hydroxyalkyl sidechains at the C-4 position of theA ring were designed as metabolically stable analogs of4-hydroxyestradiol, a catechol estrogen.These synthetic steroids would facilitate investigations on thepotential biological role of catecholestrogens and also enable further examination of the structural andelectronic constraints onthe A ring in the interaction of estrogens with the estrogen receptor.Catechol estrogens areimplicated as possible causative agents in estrogen-inducedtumorigenesis. 4-Hydroxyestradiolhas weaker affinity for the estrogen receptor and exhibits lowerestrogenic activity in vivo; onthe other hand, the catechol estrogens are prone to further oxidativemetabolism and can formreactive intermediates. This report describes the synthesis andinitial biochemical evaluationof 4-(hydroxyalkyl)estrogens and 4-(aminoalkyl)estradiols.The 4-(hydroxyalkyl)estrogens wereprepared by oxidative hydroboration of 4-alkenylestradiols. Thealkenylestradiols were obtainedvia a Stille cross-coupling between a MOM-protected 4-bromoestradioland an alkenylstannane.The (4-aminoalkyl)estrogens were prepared from thehydroxyalkyl derivatives with phthalimideunder Mitsunobu conditions. The substituted estradiols wereevaluated for estrogen receptorbinding activity in MCF-7 human mammary carcinoma cells, and4-(hydroxymethyl)estradiol1 exhibited the highest affinity with an apparentEC50 value of 364 nM. The relativeactivitiesfor mRNA induction of the pS2 gene in MCF-7 cell cultures by the4-(hydroxyalkyl)estrogensclosely parallel the relative binding affinities.4-(Hydroxymethyl)estradiol 1 did notstimulatethe growth of MCF-7 cells at concentrations up to 1 μM. Thus,4-(hydroxymethyl)estradiol 1exhibited similar estrogen receptor affinity as the catechol estrogen,4-hydroxyestradiol, andmay prove useful in the examination of the biological effects of4-hydroxyestrogens.
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