Biological Evaluation of Novel Cyclopropyl Analogues of Stilbene, Stilbenediol, and Phenanthrene for Estrogenic and Antiestrogenic Activity

The triphenylethylene-type antiestrogens, such as tamoxifen, are known to be useful in the treatment of estrogen/dependent tumors. However, these compounds display mixed estrogen agonist/antagonist activity which may limit their therapeutic effectiveness. This problem of mixed activity led to the synthesis and identification of a cyclopropyl derivative of cis-stilbene which we have named Analog I. This compound (1,1–dichloro-cis-2,3-diphenylcyclopropane) displayed only antiestrogenic activity in the mouse. The present study was designed to evaluate cyclopropyl derivatives of Analog II for estrogenic and antiestrogenic activity in the rat using the standard 3-d uterotropic assay and the uterine cytoplasmic estrogen receptor assay. Five compounds (B–F) which are cyclopropyl derivatives of stilbene, stilbenediol, and phenanthrene were evaluated in this study. Three of the compounds (B–D) displayed neither estrogenic nor antiestrogenic activity in the rat. The relative estrogenic activities of E and F were 11.3 and 1.5%, respectively, of diethylstilbestrol in the uterotropic assay, and 39 and 6.2%, respectively, of estradiol in the estrogen receptor assay. Neither E nor F was found to display antiestrogenic activity in the rat. The results indicate that the relative estrogenic and receptor binding activities of E and F are similar to those previously observed in the mouse, while B–D appear to be inactive in both species.