In vitro estrogenic actions in rat and human cells of hydroxylated derivatives of D16726 (zindoxifene), an agent with known antimammary cancer activity in vivo.

A series of 2-phenyl-1-ethyl-3-methylindoles with or without a hydroxyl group in the para position of the phenyl ring and the 5 or 6 position of the indole nucleus were compared with 17 beta-estradiol in the stimulation of (a) prolactin production in rat pituitary cells in primary culture, (b) progesterone receptor synthesis in MCF-7 cells, and (c) proliferation of MCF-7 cells. All compounds were less active than estradiol but all derivatives including D15414, the hydroxylated metabolite of D16726 (zindoxifene, a known antitumor agent against mammary cancer) were fully estrogenic. Hydroxyl groups at the para position of the phenyl ring and 6 position of the indole nucleus conferred the highest estrogen potency [ED50 (drug concentration producing 50% of maximum activity) in all assays around 10(-10) M]. Moving or eliminating the hydroxyl on the indole ring markedly reduced the estrogen potency; however, an even more dramatic reduction in estrogenic activity was produced by removing the hydroxyl of the phenyl ring.