Studies on Heterocyde-Based Pure Estrogen Antagonists
| Autor: | E. von Angerer, S. Leichtl, C. Biberger |
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| Rok vydání: | 1995 |
| Předmět: |
Transcriptional Activation
Agonist Stereochemistry medicine.drug_class Drug Resistance Antineoplastic Agents Breast Neoplasms In Vitro Techniques General Biochemistry Genetics and Molecular Biology Mice Structure-Activity Relationship chemistry.chemical_compound History and Philosophy of Science Endocrine Glands Amide Tumor Cells Cultured medicine Animals Humans Structure–activity relationship Moiety Benzofuran Indole test Chemistry Estrogen receptor binding General Neuroscience Estrogen Antagonists Benzothiophene Tamoxifen Receptors Estrogen Female HeLa Cells |
| Zdroj: | Annals of the New York Academy of Sciences. 761:176-191 |
| ISSN: | 1749-6632 0077-8923 |
| DOI: | 10.1111/j.1749-6632.1995.tb31378.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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