Antiestrogenically Active 1,1,2-Tris(4-hydroxyphenyl)alkenes without Basic Side Chain:  Synthesis and Biological Activity

Abstract

C2-Alkyl substituted derivatives of the 1,1,2-tris(4-hydroxyphenyl)ethene 3a (alkyl = Me (3b), Et (3c), Prop (3d), But (3e)) were synthesized by reaction of 1,2-bis(4-methoxyphenyl)ethanone with the appropriate alkyl halide, followed by a Grignard reaction with 4-methoxyphenylmagnesium bromide, dehydration with phosphoric acid or hydrobromic acid, and ether cleavage with BBr(3). The compounds were tested for estrogen receptor (ER) binding affinity in a competition experiment with radio labeled estradiol ([(3)H]-E2) and for gene activation on the ER-positive MCF-7-2a cell line. All compounds showed high receptor binding affinity (RBA-value: 3b (52.1%) > 3a (45.5%) > 3c (29.6%) > 3d (4.03%) > 3e (0.95%)). The tests on hormone dependent MCF-7-2a breast cancer cells, stably transfected with the plasmid ERE(wtc)luc, revealed that all 1,1,2-tris(4-hydroxyphenyl)ethenes antagonized the effect of 1 nM estradiol (E2). The compounds 3b (IC(50) = 15 nM) and 3c (IC(50) = 10 nM) were equal in their effects to 4-hydroxytamoxifen (4OHT) (IC(50) = 7 nM). Agonistic effects were low. Only 3a and 3b activated the luciferase expression (relative activation at 1 microM: 3a 60%; 3b 35%). Despite their highly antagonistic potency, the 1,1,2-tris(4-hydroxyphenyl)ethenes showed only low cytotoxic properties on the hormone sensitive MCF-7 cell line.

Structure−Function Relationships of Estrogenic Triphenylethylenes Related to Endoxifen and 4-Hydroxytamoxifen

“…Both compounds 1,1,2-Tris(4-hydroxyphenyl)but-1-ene (designated as 3 in this study) and 1,1-Bis(4,4′-hydroxyphenyl)-2-phenylbut-1-ene (designated as 15 in this study) produced weak cytotoxic effects only at concentrations above 5 uM which were well beyond the concentration range used in our study. Thus it is possible that the variation in findings between our laboratory and that of Gust and coworkers 25, 26 might be due to differences in our in vitro model systems and our experimental design.…”

“…1,1,2-Tris(4-hydroxyphenyl)but-1-ene ( 3 ) was synthesized according to the method of Lubczyk, Bachmann and Gust 26.…”

Synthesis and evaluation of 2-halogenated-1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylenes as potential estrogen receptor-targeted radiodiagnostic and radiotherapeutic agents

“…As part of our program to develop new agents for the diagnosis 45 and treatment of hormone responsive breast and ovarian cancer, 46 we have focused on the preparation and evaluation of radio-iodin- 47 ated estrogens. Our strategy is based on the mechanism of action of 48 the estrogens that involves selective binding of ligands to the hor- 49 mone receptor within the nuclear compartment of the cell [1][2][3][4][5][6].…”

“…104 The synthetic strategy was based upon the general synthesis of 105 triarylethylenes [44,45] (Scheme 1). It was of further interest 106 because the preparation of 1,1,bis(4-hydroxyphenyl)-2-(3-hydroxy 107 phenyl)ethylenes, unlike the corresponding 2-(4-hydroxyphenyl) 108 isomers, had not been well described [46]. Although one can halo- warmed to ambient temperature and ice water (10 mL) was added.…”

“…399 The resulting mixture was partitioned between EtOAc (300 mL) and lation of the bromo-derivative followed by addition of iodine [44]. ligands [46]. The van der waals radii and hydrophobic constants 772 for Br-and I-are similar to those for a methyl group [66].…”