11-BETA-AMIDOALKOXYPHENYL ESTRADIOLS, A NEW SERIES OF PURE ANTIESTROGENS

11 beta-Amidoalkoxyphenyl estradiols, a series of new antiestrogens, have been prepared and compared with tamoxifen (TAM) and 4-hydroxytamoxifen (OH-TAM). In vitro, these compounds were up to 20 times as active as OH-TAM on estradiol (E2)-stimulated MCF-7 cells. Unlike TAM or OH-TAM which were inactive, they displayed potent growth inhibitory effects on MCF-7 cells stimulated by a cocktail of epidermal growth factor and platelet derived growth factor. One of the most active compounds, 5e, was tested in vivo for its antiuterotrophic and antitumoral activities: it proved to be fully antiuterotrophic at 3 mg/kg subcutaneously in mice while being devoid of any uterotrophic activity. It inhibited the E2-induced growth of MCF-7 tumors implanted in nude mice and prevented the partial agonistic activity of TAM on MCF-7 tumor growth in ovariectomized mice. Moreover, on MCF-7 variant tumors, 5e, unlike TAM, did not display any proliferative activity, but inhibited the TAM-induced growth. Overall, these results show that this new series of compounds displays an improved activity profile compared with that of TAM, on tests relevant to human breast cancer treatment.