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The syntheses of the hexestrol derivatives 3,4-bis-(3'-hydroxyphenyl)hexane (4a), 3,4-bis(4'-fluoro-3'-hydroxyphenyl)hexane (4b), 3,4-bis(3',4'dihydroxyphenyl)hexane (4c), and 3,4-bis(3',4'-diacetoxyphenyl)hexane (4d) are described. All compounds showed a marked, competitive inhibition of the estradiol receptor interaction (Ka4c greater than Ka4a greater than Ka4d greater than Ka4b). Evaluated in the mouse uterine weight test compounds 4c and 4d almost reached the estrone effect, whereas 4a and 4b did not produce full uterotrophic response. Compounds 4a--d antagonized the estrone stimulated uterine growth of the immature mouse. Compound 4a (NSC-297170) exhibited a specific, dose-related growth inhibition of the estrogen responsive MCF-7 human breast tumor cell line. Tested on the 9,10-dimethyl-1,2-benzanthracene-induced hormone-dependent mammary adenocarcinoma of the Sprague-Dawley rat all compounds showed marked inhibition of tumor growth. As in all experiments compounds 4a and 4b, which is resistant to hydroxylation in 4'-position exhibited an identical pattern of action, which is different from that shown by compound 4c, the effect of compound 4a cannot be explained by its possible catechol metabolite 4c.

trans-1,2-Bis(trifluoromethyl)-1,2-bis(4- and 3-hydroxyphenyl)ethenes 2 and 4 were prepared by reductive coupling (TiCl4/Zn/pyridine) of the methoxy-substituted alpha, alpha, alpha-trifluoroacetophenones, separation of the resulting cis- and trans-stilbene derivatives, and ether cleavage with BBr3. The cis-stilbenes were catalytically hydrogenated to give meso-1,1,1,4,4,4-hexafluoro-2,3-bis(4- and 3-hydroxyphenyl)butanes 6 and 8. Compounds 2, 4, 6, and 8 showed 2- to 10-fold increased binding affinities for the estradiol receptor (E2R) and enhanced estrogenicity in the uterine weight test of the immature mouse compared to their unfluorinated analogues. Compound 8 exhibited a 46% inhibition of the estrone-stimulated uterine growth. Antitumor activity was evaluated with use of the transplantable, hormone-dependent MXT mammary tumor of the BD2F1 mouse. All compounds showed tumor growth inhibitory activity corresponding to their RBA values. The most interesting compound 8 led to a significant inhibition of the tumor growth on the DMBA-induced hormone-dependent mammary carcinoma of the Sprague-Dawley rat.

With the erythro-hexestrol derivative 2 as the starting material, a variety of cytotoxic linked hexestrol (HEX) compounds were prepared including the HEX-N-lost derivative 36, the HEX-(chloroethyl)nitrosourea 38, the HEX-cyclophosphamide 44, and the HEX-epoxide 68. Relative binding affinity to estradiol receptors were in the magnitude of 1%, similar to that of comparable diethylstilbestrol compounds. HEX derivatives with long polyether spacers (64, 65, 70, 71) showed no significant decrease in binding affinity in contrast to derivatives with other bulky side chains.