2-Phenylbenzo[b]furans: relationship between structure, estrogen receptor affinity and cytostatic activity against...

A number of 2-(4-hydroxyphenyl)benzo[b]furans with a hydroxy group in position 5 or 6 and a short alkyl group at C-3 were synthesized from appropriate 1,2-diarylethanones and studied for their estrogen receptor affinity. The relative binding affinities in the 5-hydroxy series were higher than those of 6-hydroxy derivatives by a factor of 10. The trifluoroethyl and the propyl derivatives displayed the best relative binding affinity values (33 (15a) and 20 (12a); 17 beta-estradiol = 100). All benzofurans with high receptor affinity were tested for specific cytostatic activity using hormone-sensitive human MCF-7 mammary tumor cells and hormone-independent MDA-MB 231 cells. 5-Hydroxy derivatives with an ethyl (11a) or a propyl (12a) group completely inhibited the growth of MCF-7 cells at a concentration of 5 microM (tamoxifen: 70% inhibition). Since the cytostatic activity in MDA-MB 231 cells was much lower, an anti-tumor effect mainly mediated by the estrogen receptor has to be assumed. In the mouse uterine weight test these compounds gave rise to a partial estrogen antagonism which may account for the inhibitory effect in estrogen-sensitive tumor cells.