Influence of new hydroxylated Triphenylethylene (TPE) derivatives on estradiol binding to uterine cytosol

Abstract

Twelve homologous triphenyl acrylonitrile derivatives with a p-OH or P-CH 3 group on one or more of the phenyl rings were synthesized in order to assess the relative influence of each position on binding to the estrogen receptor (ER) and on inhibition of prostaglandin synthetase (PGS). Their relative binding affinities (RBAs) for [ 3H]estradiol (E 2)-labeled ER were compared at 0 and 25°C in mouse and rat uterus cytosol with those of tamoxifen derivatives, cyclofenil and diethylstilbestrol. RBAs in both species were closely correlated ( r = 0.92) although the RBAs were about twice as high in the mouse as in the rat. The unsubstituted skeleton had an RBA of ⪡ 0.1 (estradiol = 100). An OH-group in R 1 or R 2 (Fig. 1) engendered very low affinity whereas an OH-group in R gave rise to a compound with an RBA equivalent to that of E 2, emphasizing the importance of this position in the interaction with ER. Compounds with an additional OH-group in R 1 or R 2 were significantly better competitors than E 2. No further increase in RBA was noted with the trihydroxy derivative. The effect of the introduction of a hydrophobic CH 3-group decreased affinity as expected in R, but also in position R 1 unless a second OH-group was present in R 2. None of the 12 test-compounds competed significantly for binding to the “anti-estrogen binding site” in rat kidney supernatant. Although polar groups were not necessary for inhibition of PGS, inhibition was enhanced by the presence of a hydroxy group in R or R 1 (but not R 2). Even greater inhibition was obtained by the further introduction of a CH 3-group in R 1 or R respectively. The conformations of these derivatives are compared to those of known estrogen ligands and anti-inflammatory agents in order to obtain further information on these protein recognition sites.