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

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Abstract
The syntheses of symmetrically 1,2''-disubstituted derivatives of 1,1,2,2-tetramethyl-2,2-bis(4-hydroxyphenyl)ethane (1) and of 5,5''-, and 6,6''-disubstituted derivatives of 1,1,2,2-tetramethyl-1,2-bis(3-hydroxyphenyl)ethane (6) are described (1 and 6 are strong antiestrogens with mammary tumor inhibiting activity exhibiting only slight estrogenic properties): (2,2''-substituents) F (2), Cl (3), OCH3 (4), CH3 (5); (5,5''-substituents) Cl (7); (6,6''-substituents) F (8), Cl (9), OCH3 (10), CH3 (11). The synthesis of 1-11 was accomplished by reductive coupling of the corresponding 2-phenyl-2-propanols with TiCH3 and LiAlH4. The binding affinity of the compounds to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. With the exception of 7 and 10 all other compounds showed relative binding affinity (RBA) values between 0.5 and 6.4% that of estradiol, 2 (RBA value 6.4), and 8 and 9 (4.0 and 3.5), exceeding those of the corresponding unsubstituted 1 and 6 (3.6 and 3.0). Compounds exhibiting RBA values of > 2.5% were evaluated in the mouse uterine weight test. The substituted derivatives showed an increase in uterotrophic and a decrease in antiuterotrophic activity compared to 1 and 6. Compound 2 showed a strong, dose-dependent inhibition on the DMBA-induced hormone-dependent mammary tumor of the SD-rat, exceeding that of the parent compound 1. At a dose of 5 mg/kg per day, 2 reduced total tumor area by 47% and caused a complete remission in 74% of the tumors.

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