Synthesis and antiestrogenic activity of diaryl thioether derivatives.
The reaction of 1,2-diarylethanol and mercapto side chain catalyzed by ZnI2 was used as a key step in the short (three to five steps) and efficient synthesis of 17 diaryl thioether derivatives. Several of these compounds contain a methyl butyl amide chain and an hydroxyaryl moiety, respectively, for antiestrogenic activity and binding affinity on estrogen receptor. No binding affinity for crude cytosolic preparation of the estrogen receptor was observed for compounds without phenolic group, while a low affinity (0.01-0.05%) was measured for mono- or diphenol derivatives. Like the pure steroidal antiestrogen EM-139, these novel nonsteroidal compounds did not exert any stimulatory effect on cell proliferation of (ER+) ZR-75-1 human breast cancer cells and partially reversed the amplitude of the stimulatory effect induced by estradiol on this (ER+) cell line. No proliferative or antiproliferative effect on (ER-) MDA-MB-231 human breast cancer cells was also observed for three of these compounds (39-41). Among the newly synthesized nonsteroidal compounds, the thioether derivative 41 (N-butyl-N-methyl-13,14-bis(4'-hydroxyphenyl)-12-thiatetradecanamide+ ++), with a long methylbutylalkanamide side chain and a diphenolic nucleus, was selected as the best antiestrogenic compound. However, this compound was 100-fold less antiestrogenic in (ER+) ZR-75-1 cells than the steroidal antiestrogen EM-139.
Poirier
D
D
Laboratory of Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
Auger
S
S
Mérand
Y
Y
Simard
J
J
Labrie
F
F
D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D010636:Phenols; D013440:Sulfides; C064480:EM 139; C086900:N-butyl-N-methyl-13,14-bis(4'-hydroxyphenyl)-12-thiatetradecanamide; D004958:Estradiol