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In Vitro Estrogenic Actions in Rat and Human Cells of Hydroxylated Derivatives of D16726 (Zindoxifene), an Agent with Known Antimammary Cancer Activity in Vivo¹

Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison, WI 53792

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 17ß-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.

¹ Supported in part by NIH Grant CA-32713.

² To whom requests for reprints should be addressed, at Department of Human Oncology, University of Wisconsin Clinical Cancer Center, 600 Highland Avenue, Madison, WI 53792.

Received 6/29/87. Revised 10/29/87. Accepted 11/11/87.

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