Ring-substituted 1,1,2,2-tetraalkylated 1,2-bis(hydroxyphenyl)ethanes. 4. Synthesis, estrogen receptor binding affinity, and evaluation of antiestrogenic and mammary tumor inhibiting activity of symmetrically disubstituted 1,1,2,2-tetramethyl-1,2-bis(hydroxyphenyl)ethanes

Abstract

The title compds. I (R = R1 = H, Cl, F, Me, MeO, OH) prepd. by coupling the corresponding substituted 2-(methoxyphenyl)-2-propanol using TiCl3/LiAlH4 and subsequent ether cleavage of the products, were evaluated for estrogenic, antiestrogenic, and mammary tumor-inhibiting activities. The relative binding affinity was detd. by displacement of [3H]estradiol after incubation with calf uterine cytosol. Estrogenic and antiestrogenic activities were detd. by stimulation of uterine growth and inhibition of the uterine growth stimulated by estrone. Tumor-inhibiting effect was detd. by using the DMBA-induced, hormone-dependent mammary adenocarcinoma of the SD-rat. Most compds. showed an increase in uterotrophic and a decrease in antiuterotrophic activity compared to the unsubstituted ones. 2,3-Bis(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane (I, R = 2-fluoro; R1 = 4-OH) [96826-17-4] showed a strong, dose-dependent antitumor activity exceeding that of the parent 2,3-bis-(4-hydroxyphenyl)-2,3-dimethylbutane (I, R = H; R1 = 4-OH) [74385-27-6]; at 5 mg/kg/day reduced total tumor area by 47% and caused a complete remission in 74% of the tumors. Structure-activity relations are discussed.