Synthesis and biological activities of thioether derivatives related to the antiestrogens tamoxifen and ICI 164384.
The catalyzed coupling reaction of activated alcohol and mercaptan was used for the short and efficient synthesis of 14 thioether compounds. Two types of side chains, the methyl butyl alkylamide related to the pure steroidal antiestrogen ICI 164384 and the dimethylamino ethyloxy phenyl related to the clinically used nonsteroidal antiestrogen tamoxifen, were introduced by a thioether link on two types of nuclei (triphenylethane or estradiol). The new thioether derivatives were tested to assess their relative binding affinity for the estrogen receptor and their estrogenic or antiestrogenic activity in the ZR-75-1 (ER+) cell line. The results indicate that of the three types of compounds studied, only the nonsteroidal derivatives with an alkylamide side chain possess antiestrogenic activity. In the steroidal series, displacement of the alkylamide side chain from the 7 to the 6 position produced compounds with chemical characteristics similar to ICI 164384 or EM-139 but without antiestrogenic activity. In the nonsteroidal series of compounds with an aryl side chain, compounds with estrogenic activity were obtained. One compound, a nonsteroidal derivative with a methyl butyl alkylamide side chain 20, possesses a relative binding affinity for the estrogen receptor identical to EM-139 (1.1 and 1.2%, respectively) and a relatively good antiestrogenic activity that is 10-fold lower than EM-139 (IC50 values of 250 and 25 nM, respectively). This nonsteroidal thioether with an alkylamide side chain is free of estrogenic activity.
Auger
S
S
MRC Group in Molecular Endocrinology, CHUL Research Center, Québec, Canada.
Mérand
Y
Y
Pelletier
J D
JD
Poirier
D
D
Labrie
F
F
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D053284:Polyunsaturated Alkamides; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; C051781:ICI 164384