{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:54:01Z","timestamp":1785434041629,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003827","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["SNN 139323"],"award-info":[{"award-number":["SNN 139323"]}],"id":[{"id":"10.13039\/501100003827","id-type":"DOI","asserted-by":"publisher"}]},{"award":["SNN 139323"],"award-info":[{"award-number":["SNN 139323"]}],"id":[{"id":"https:\/\/ror.org\/03g2am276","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency","doi-asserted-by":"crossref","award":["N1-0234"],"award-info":[{"award-number":["N1-0234"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency","doi-asserted-by":"crossref","award":["P3-0449"],"award-info":[{"award-number":["P3-0449"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"crossref"}]},{"award":["N1-0234"],"award-info":[{"award-number":["N1-0234"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P3-0449"],"award-info":[{"award-number":["P3-0449"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Aldo\u2013keto reductase isoforms AKR1C1\u20133 and 17\u03b2-hydroxysteroid dehydrogenase 1 and 2 (17\u03b2-HSD1 and 17\u03b2-HSD2) are key enzymes in steroid metabolism and validated targets in hormone-dependent cancers. Methods: In this study, \u039415- and 15\u03b2-substituted estrone derivatives were evaluated as inhibitors of AKR1C1\u20133 and 17\u03b2-HSD1 using enzymatic assays, cell viability assaysand computational modeling. Cellular uptake of the fluorescent estrone-based inhibitor was investigated using confocal microscopy. Results: The \u039415-estrone derivative showed potent and selective inhibition of 17\u03b2-HSD1 in the low nanomolar range, while 15\u03b2-O-propargyl and 15\u03b2-azide derivatives exhibited dual inhibitory activity against 17\u03b2-HSD1 and AKR1C2. The \u039415- and 15\u03b2-azide derivatives reduced cell viability in hormone-dependent breast, endometrial, and ovarian cancer cell lines in the sub- to low-micromolar range. A BODIPY-labeled 15\u03b2-O-propargyl analogue retained submicromolar inhibitory potency toward 17\u03b2-HSD1, representing the first fluorescent estrane-based inhibitor with preserved biological activity. Confocal microscopy confirmed efficient cellular uptake and predominant cytosolic localization in MCF-7 cells. Conclusions: These findings identify \u039415- and 15\u03b2-modified estrone derivatives as promising single- and dual-target inhibitors and introduce a fluorescent probe suitable for investigating intracellular steroid metabolism in hormone-dependent malignancies.<\/jats:p>","DOI":"10.3390\/cancers18121889","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T09:25:17Z","timestamp":1781083517000},"page":"1889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Steroid-Metabolizing Enzymes with 15\u03b2-Substituted Estrone Analogues: Dual Discovery of AKR1C2\/17\u03b2-HSD1 Inhibitors and a Fluorescent 17\u03b2-HSD1 Ligand"],"prefix":"10.3390","volume":"18","author":[{"given":"Vivien","family":"Resch","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, University of Szeged, D\u00f3m t\u00e9r 8, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Gjorgoska","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Hafner","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildik\u00f3","family":"Bacsa","sequence":"additional","affiliation":[{"name":"Institute of Pharmacognosy, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0799-1908","authenticated-orcid":false,"given":"Benjamin","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Institute of Pharmacognosy, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toma\u017e","family":"B\u00fcdefeld","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0074-3472","authenticated-orcid":false,"given":"Attila","family":"Hunyadi","sequence":"additional","affiliation":[{"name":"Institute of Pharmacognosy, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"},{"name":"HUN-REN-SZTE Biologically Active Natural Products Research Group, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildik\u00f3","family":"Huli\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Szeged, K\u00f6z\u00e9p fasor 52, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8416-2052","authenticated-orcid":false,"given":"M\u00f3nika","family":"Kiricsi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Szeged, K\u00f6z\u00e9p fasor 52, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5408-1748","authenticated-orcid":false,"given":"G\u00e1bor","family":"Paragi","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Szeged, D\u00f3m t\u00e9r 8, H-6720 Szeged, Hungary"},{"name":"Institute of Physics, University of P\u00e9cs, H-7624 Pecs, Hungary"},{"name":"Department of Theoretical Physics, University of Szeged, Tisza L. krt. 84-86, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3453-4081","authenticated-orcid":false,"given":"Tea Lani\u0161nik","family":"Ri\u017ener","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4494-1817","authenticated-orcid":false,"given":"Erzs\u00e9bet","family":"Merny\u00e1k","sequence":"additional","affiliation":[{"name":"Institute of Pharmacognosy, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ri\u017ener, T.L., and Romano, A. 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