A number of 2-(4-hydroxyphenyl)benzo[b]
thiophenes with a hydroxy group in position 5 or 6 and a short alkyl group at C-3 were synthesized and studied for their
estrogen receptor affinities. Relative binding affinities (RBA) for the calf uterine
estrogen receptor ranged from 3 to 60 (
17 beta-estradiol = 100). The highest RBA values were found with ethyl derivatives [3 (5-
OH): 60; 7 (6-
OH): 28]. In accord with their receptor affinity, all benzothiophenes exhibited endocrine activity in the immature mouse uterine weight test. At doses of 0.25-7.0 mg/kg
body weight, they showed partial
estrogen antagonism and usually weak
estrogenic effects. All compounds entered tests with
hormone-sensitive human MCF-7
breast cancer cells. At concentrations of 1 microM and higher, most of the derivatives displayed significant inhibition of cell growth. These results prompted us to test them in vivo for
cytostatic activity using
hormone-dependent MXT mouse mammary
tumors. The 5-hydroxy derivatives 3 and 4 strongly inhibited the growth of these
tumors. After 4 weeks of treatment with 3 x 4.2 mg/kg of compound 3, the average
tumor weight was reduced by 83% vs control (
tamoxifen at equimolar dose: 74%). The 6-hydroxy derivative 7 required higher doses (25 mg/kg) to give rise to the same antitumor effect. At the end of
therapy, no increase of uterine weight due to an
estrogenic effect was observed. We assume therefore that the
antineoplastic activity of these compounds in this
tumor model is due mainly to their
estrogen antagonism.