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.
The syntheses of symmetrically 2,2'-disubstituted derivatives of 1,1,2,2-tetramethyl-1,2-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 TiCl3 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 greater than 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.
Hartmann
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Schwarz
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Heindl
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Schönenberger
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D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000138:chemical synthesis*; D005260:Female; D006589:Hexestrol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D006589:Hexestrol; D004958:Estradiol; C039150:1,1,2,2-tetramethyl-1,2-bis(4'-hydroxyphenyl)ethane