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.
Robinson
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SP
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Koch
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R
Jordan
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VC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007211:Indoles / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011388:Prolactin / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000187:drug effects; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D007211:Indoles; D011980:Receptors, Progesterone; C041791:zindoxifene; D011388:Prolactin