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However, despite the fact that it exerts antagonistic effects on the ER\u03b1, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2H-pyrrol-2-ones were synthesized and evaluated by using ER\u03b1- and phenotype-based screening assays. Compounds 32 and 35 inhibited 17\u03b2-estradiol (E2)-stimulated ER\u03b1-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound 32 regulated E2-stimulated ER\u03b1-mediated transcription by partial antagonism, whereas compound 35 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 32 and 35 caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0\/G1 phases. Interestingly, compound 35 suppressed the functional activity of ER\u03b1 in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound 35 showed a relatively low binding affinity with ER\u03b1. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ER\u03b1. Clinically relevant, a possible combinatory therapy with compound 35 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.<\/jats:p>","DOI":"10.3390\/cancers14215174","type":"journal-article","created":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T20:43:50Z","timestamp":1666557830000},"page":"5174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0047-1131","authenticated-orcid":false,"given":"Miguel","family":"Guerra-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Farmacolog\u00eda Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biom\u00e9dicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe F\u00edsico s\/n, 35016 Las Palmas de Gran Canaria, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priscila","family":"L\u00f3pez-Rojas","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Instituto Universitario de Bio-Org\u00e1nica Antonio Gonz\u00e1lez (IUBO AG), Universidad de La Laguna (ULL), Avda. Astrof\u00edsico Fco. S\u00e1nchez 2, 38206 La Laguna, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1ngel","family":"Amesty","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Instituto Universitario de Bio-Org\u00e1nica Antonio Gonz\u00e1lez (IUBO AG), Universidad de La Laguna (ULL), Avda. Astrof\u00edsico Fco. S\u00e1nchez 2, 38206 La Laguna, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haid\u00e9e","family":"Aranda-Tav\u00edo","sequence":"additional","affiliation":[{"name":"Farmacolog\u00eda Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biom\u00e9dicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe F\u00edsico s\/n, 35016 Las Palmas de Gran Canaria, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0707-7444","authenticated-orcid":false,"given":"Yeray","family":"Brito-Casillas","sequence":"additional","affiliation":[{"name":"Farmacolog\u00eda Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biom\u00e9dicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe F\u00edsico s\/n, 35016 Las Palmas de Gran Canaria, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5279-7099","authenticated-orcid":false,"given":"Ana","family":"Est\u00e9vez-Braun","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Instituto Universitario de Bio-Org\u00e1nica Antonio Gonz\u00e1lez (IUBO AG), Universidad de La Laguna (ULL), Avda. 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