Carboxylic acid analogues of tamoxifen: (Z)-2-[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine. Estrogen receptor affinity and estrogen antagonist effects in MCF-7 cells

The triarylethylene estrogen mimetic (E,Z)-4-[1-(p-hydroxyphenyl)-2-phenyl- 1-butenyl]phenloxyacetic acid (4) represents a novel class of estrogen rece ptor (ER) ligands which, like tamoxifen (1), can elicit estrogen agonist an d antagonist effects, in turn, in nonreproductive and reproductive tissues. Analogues of 4, incorporating structural features shown previously in tria rylethylenes to improve ER affinity and estrogen antagonist properties, wer e prepared with the ultimate aim of identifying substances with improved es trogenicity exclusive of reproductive tissues. Thus, the side chain of 4 wa s elongated to give oxybutyric acid 13, which was further altered by (a) re positioning of its p-hydroxyl to the neighboring m-position (12) and (b) et hylenic bond reduction (14). Also, the p-hydroxyl group and oxyacetic acid groups of 4 were, in turn, shifted to the neighboring m-positions, affordin g 8 and 9. Oxybutyric acid analogue 13 had about 2 times the affinity for h uman ER alpha as 4, and its antiproliferative effect in MCF-7 cells was gre ater than that of 1. Dihydro analogue 14, which was conformationally simila r 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 an tiproliferative efficacy was retained. Modest ER affinity and antiprolifera tive potency were seen with 8, in which phenolic and phenyl rings were tran s to one another, but 9, in which these rings were cis, was inactive. Our f indings indicate that two-carbon side-chain elongation and/or m-positioning of the hydroxyl group in 4 affords analogues with dominant estrogen antago nist effects in MCF-7 cells.