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

Abstract

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.

Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

“…Oxyacetic analogues of 2a had been reported to act as estrogen antagonists in MCF-7 cells. 31,32 In series III, compounds 19a and 19b, containing a 4-oxyacetic acid substituent in place of the acrylic acid in 11b and 11c, along with compound 22, did not have antiproliferative activity at concentrations up to 20 μM (as was observed for the oxyacetic analogue of 2a 32 ).…”

“…This binding value for 22 is an improvement on reported values for the corresponding oxybutyric acid analogue of 2a. 32 In order to assist us in the rationalisation of the  selectivity observed for the ER binding results obtained for these benzoxepin compounds, the ER binding effects of the core structure 9c…”

Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs

“…Their masses were confirmed via their molecular ion peaks [M+H] + and [M+H+2] + due to the presence of chlorine atoms in all compounds. As previously employed in similar work in the literature, compounds were assayed biologically as E-Z mixtures [33][34][35][36].…”

“…The residue was dissolved in an aqueous solution containing 30% hydrochloric acid (500 mL) and then extracted with dichloromethane (120 mL × 6). The organic layers were combined and dried over anhydrous Na 2 SO 4 , concentrated in vacuo, and further purified by silica gel column chromatography or a Biotage ® Isolera™ flash purification system using Biotage ® KP-Sil SNAP columns (dichloromethane) to yield compounds 1-4 [34].…”

Advances in the Science of Estrogen Receptor Modulation

“…The estrogen receptor modulating ability of this compound class could be changed from agonist to antagonist by simple structural modifications. The introduction of the phenolic OH at the meta position and/or the two carbon elongation of the side chain substituent results in the compounds such as 17 and 18 with selective estrogen antagonistic activity in MCF-7 cells (RBA, relative binding affinity 17, 0.35, 18, 2.5 and IC 50 1700, 235 nM) [145]. The estrogen antagonistic effects of the compounds are 720 and 20 IC 50 nM.…”