Five hydroxylated analogues of tamoxifen [1, (Z)-2-[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine] and its geometric isomer were prepared by reaction of protected hydroxy-alpha-ethyldeoxybenzoins with 4-[2-dimethylamino) ethoxy]phenylmagnesium bromide, followed by acid-catalyzed dehydration-deprotection and chromatographic separation of isomer mixtures. Estrogen receptor binding affinity and estrogenic and antiestrogenic activity of each of the compounds were determined in the rat, in comparison with 4-hydroxytamoxifen (2). The new compounds had a wide range of receptor binding affinities, with that of 3-hydroxytamoxifen (6c), the most strongly bound, approaching that of estradiol. The trans isomers 6a,b were more strongly bound than were the cis isomers 7a,b. Antiestrogenic activity was seen in all compounds except 7b. This was also true for estrogenic activity, except that in 6c this activity was also substantially reduced. Maximal antiestrogenic effectiveness of 6c occurred at a 10-fold greater daily dose (50 micrograms/rat) than that required for maximal effect of 2.

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The triarylethylene estrogen mimetic (E, Z)-4-[1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxyacetic acid (4) represents a novel class of estrogen receptor (ER) ligands which, like tamoxifen (1), can elicit estrogen agonist and antagonist effects, in turn, in nonreproductive and reproductive tissues. Analogues of 4, incorporating structural features shown previously in triarylethylenes to improve ER affinity and estrogen antagonist properties, were prepared with the ultimate aim of identifying substances with improved estrogenicity exclusive of reproductive tissues. Thus, the side chain of 4 was elongated to give oxybutyric acid 13, which was further altered by (a) repositioning of its p-hydroxyl to the neighboring m-position (12) and (b) ethylenic bond reduction (14). Also, the p-hydroxyl group and oxyacetic acid groups of 4 were, in turn, shifted to the neighboring m-positions, affording 8 and 9. Oxybutyric acid analogue 13 had about 2 times the affinity for human ERalpha as 4, and its antiproliferative effect in MCF-7 cells was greater than that of 1. Dihydro analogue 14, which was conformationally similar to cis-13, had very low ER affinity and antiestrogenicity, and m-hydroxy analogue 12 also had reduced ER affinity and potency, but its MCF-7 cell antiproliferative efficacy was retained. Modest ER affinity and antiproliferative potency were seen with 8, in which phenolic and phenyl rings were trans to one another, but 9, in which these rings were cis, was inactive. Our findings indicate that two-carbon side-chain elongation and/or m-positioning of the hydroxyl group in 4 affords analogues with dominant estrogen antagonist effects in MCF-7 cells.

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