Ring-substituted 1,2-dialkylated 1,2-bis(hydroxyphenyl)ethanes. 2. Synthesis and estrogen receptor binding affinity of 4,4'-, 5,5'-, and 6,6'-disubstituted metahexestrols

Article abstract of DOI:10.1021/jm00371a004

The synthesis of symmetrically 4,4'-, 5,5'-, and 6,6'-disubstituted derivatives of the mammary tumor inhibiting antiestrogen metahexestrol [meso-3,4-bis(3-hydroxyphenyl)hexane] (1) are described [4,4'-disubstituents: F(2), Cl (3), Br (4), I (5), CH₂N(CH₃)₂ (6), CH₃ (7), CH₂OCH₃ (8), CH₂OC₂H₅ (9), CH₂OH (10), NO₂ (11), NH₂ (12), N(CH₃)₂ (13), COCH₃ (14), and C₂H₅ (15); 5,5'-substituents: OH (16) and Cl (17); 6,6'-disubstituents: OH (18), F (19), Cl (20), and CH₃ (21)]. The synthesis of 1-3, 16, and 19 was accomplished by reductive coupling of the propiophenones with TiCl₄/Zn and subsequent hydrogenation of the cis-3,4-diphenylhex-3-enes. Compounds 17, 18, 20, and 21 were synthesized by coupling the 1-phenyl-1-propanols with TiCl₃/LiAlH₄ and separation of the meso diastereomers, while 4-15 were obtained by substitution of metahexestrol. The binding affinity of these compounds to the calf uterine estrogen receptor was measured relative to that of [³H]estradiol by a competitive binding assay. The test compounds showed relative binding affinity (RBA) values between 15 and <0.01% that of estradiol. Only compound 21 showed an estrogen receptor binding affinity exceeding that of metahexestrol (15 and 10%, respectively). Compounds exhibiting RBA values of >0.5% were evaluated in the mouse uterine weight test. They showed a similar (2 and 12), slightly increased (19 and 21), or strongly enhanced (7 and 20) estrogenicity compared to that of metahexestrol. Compounds 1, 2, 7, 12, and 21 exhibited antiestrogenic activity inhibiting the estrone-stimulated uterine growth (24 to 60% inhibition).