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In this study, a series of 10\u2010alkoxy steroids containing a 1,4\u2010dien\u20103\u2010one moiety was synthesized via a one\u2010step dearomatization of the A\u2010ring of estradiol and an estrane derivative with a D\u2010homo lactone moiety. All compounds exhibited favorable in silico ADMET properties, while five derivatives showed significant cytotoxic activity in\u00a0vitro. The strongest effects against the estrogen\u2010positive breast cancer cell line MCF\u20107 were observed for two 10\u03b2\u2010methoxy, one 10\u03b2\u2010butoxy, and two 10\u03b2\u2010propargyloxy derivatives. The activity of the 10\u03b2\u2010butoxy\u201017\u03b2\u2010hydroxy and 10\u03b2\u2010propargyloxy\u201017\u03b2\u2010hydroxy steroids correlates with strong binding affinity toward estrogen receptor \u03b1 and inhibition of AKR1C3 and AKR1C4 enzymatic activity. Additionally, the propargyloxy derivative showed substrate\u2010like binding to human recombinant aromatase. Molecular docking results are in qualitative agreement with these findings, predicting binding modes similar to known ligands and possible hydrophobic interactions between the C\u201010 alkoxy groups and the active sites of target proteins, particularly the heme group of aromatase. These results highlight novel estrane derivatives as promising candidates for estrogen\u2010positive breast cancer therapy through combined effects involving AKR1C3 inhibition and interaction with aromatase and estrogen receptor.<\/jats:p>","DOI":"10.1111\/cbdd.70321","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T18:14:21Z","timestamp":1779819261000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel 10\u2010Alkoxy 1,4\u2010Dien\u20103\u2010One Estranes as Multitarget Anticancer Agents Against Estrogen\u2010Positive Breast Cancer"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8045-3568","authenticated-orcid":false,"given":"Ivana","family":"Kuzminac","sequence":"first","affiliation":[{"name":"Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection University of Novi Sad  Novi Sad Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9020-698X","authenticated-orcid":false,"given":"Sofija","family":"Beki\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection University of Novi Sad  Novi Sad Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Stevanovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection University of Novi Sad  Novi Sad Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Scholda","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, Department of Pharmaceutical Sciences, Clinical Pharmacy Group University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Kopp","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, Department of Pharmaceutical Sciences, Clinical Pharmacy Group University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Petri","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Department of Biology and Ecology University of Novi Sad  Novi Sad Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1058-6872","authenticated-orcid":false,"given":"An\u0111elka","family":"\u0106eli\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Department of Biology and Ecology University of Novi Sad  Novi Sad Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Saka\u010d","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection University of Novi Sad  Novi Sad Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.08.010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009594727358"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.113115"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae303"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2017.12.002"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107607"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216\u2010007\u20101559\u20106"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1211\/0022357045020"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2009.12.009"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2010.11.004"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2165\/11204810\u2010000000000\u201000000"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz382"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201600182"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.857590"},{"key":"e_1_2_9_17_1","first-page":"82","article-title":"PyMOL: An Open\u2010Source Molecular Graphics Tool","volume":"40","author":"DeLano W. 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