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 tamoxi fen, were introduced by a thioether link on two types of nuclei (triph enylethane 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(+)) cel l line. The results indicate that of the three types of compounds stud ied, only the nonsteroidal derivatives with an alkylamide side chain p ossess antiestrogenic activity. In the steroidal series, displacement of the alkylamide side chain from the 7 to the 6 position produced com pounds with chemical characteristics similar to ICI 164384 or EM-139 b ut without antiestrogenic activity. In the nonsteroidal series of comp ounds 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 t he estrogen receptor identical to EM-139 (1.1 and 1.2%, respectively) and a relatively good antiestrogenic activity that is 10-fold lower th an EM-139 (IC50 values of 250 and 25 nM, respectively). This nonsteroi dal thioether with an alkylamide side chain is free of estrogenic acti vity.