Studies on Heterocyde‐Based Pure Estrogen Antagonistsa

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Abstract
2-Phenylindoles and isosteric structures such as benzo[b]furans and benzo[b]thiophenes were used as estrogen receptor binding moiety for the syntheses of new nonsteroidal antiestrogens. The antiestrogenic potency was considerably enhanced following the introduction of polar functional groups into the side chain in position 1 (indole) or 3 (benzofuran, benzothiophene). The amino compounds could be characterized as mixed agonist/antagonists. Among the derivatives with an amide group compounds without any agonistic activity both in vitro and in vivo were identified. The amide function can be replaced by alkylthio or alkylsulfonyl groups without changing the endocrine profile very much. In this study, the estrogenic activity was determined in a new transcription assay with luciferase as the reporter. The results obtained in this assay were in very good agreement with those from the conventional mouse uterine weight test. Antitumor activity was determined in hormone-sensitive MCF-7 breast cancer cells. There was no difference in activity between partial and pure estrogen antagonists. However, the derivatives with sulfur containing side chains were much more active than the corresponding heterocycles with amino or carbamoyl functions. They reached IC50-values of about 1 nM. 2-Phenylindoles and 2-phenylbenzothiophenes were rather similar in their potencies whereas the benzofuran derivatives were less active probably due to their lower binding affinities for the ER.