| Summary: | Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds <b>32</b> and <b>35</b> inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound <b>32</b> regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound <b>35</b> caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds <b>32</b> and <b>35</b> caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound <b>35</b> suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound <b>35</b> showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound <b>35</b> may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.
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