{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:57:42Z","timestamp":1760147862162,"version":"build-2065373602"},"reference-count":64,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T00:00:00Z","timestamp":1678147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"POCI\u2014COMPETE 2020\u2014Operational Programme Competitiveness and Internationalization in Axis I\u2014Strengthening Research, Technological Development, and Innovation","award":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"],"award-info":[{"award-number":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"]}]},{"name":"FCT\u2014Foundation for Science and Technology","award":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"],"award-info":[{"award-number":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"]}]},{"name":"Portuguese NMR Network (PTNMR)","award":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"],"award-info":[{"award-number":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"]}]},{"name":"V.B.","award":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"],"award-info":[{"award-number":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"]}]},{"name":"C4-Cloud Computing Competences Center","award":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"],"award-info":[{"award-number":["Project No. 007491","Project UID\/ Multi\/00709","Infrastructure Project No. 022161","BID\/ICI-FC\/Santander Universidades-UBI\/2016","SFRH\/BD\/131059\/ 2017","CENTRO-01-0145-FEDER-000019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Steroids constitute an important class of pharmacologically active molecules, playing key roles in human physiology. Within this group, 16E-arylideneandrostane derivatives have been reported as potent anti-cancer agents for the treatment of leukemia, breast and prostate cancers, and brain tumors. Additionally, 5\u03b1,6\u03b1-epoxycholesterol is an oxysterol with several biological activities, including regulation of cell proliferation and cholesterol homeostasis. Interestingly, pregnenolone derivatives combining these two modifications were described as potential neuroprotective agents. In this research, novel 16E-arylidene-5\u03b1,6\u03b1-epoxyepiandrosterone derivatives were synthesized from dehydroepiandrosterone by aldol condensation with different aldehydes followed by a diastereoselective 5\u03b1,6\u03b1-epoxidation. Their cytotoxicity was evaluated on tumoral and non-tumoral cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, the assessment of the neuroprotective activity of these derivatives was performed in a dopaminergic neuronal cell line (N27), at basal conditions, and in the presence of the neurotoxin 6-hydroxydopamine (6-OHDA). Interestingly, some of these steroids had selective cytotoxic effects in tumoral cell lines, with an IC50 of 3.47 \u00b5M for the 2,3-dichlorophenyl derivative in the breast cancer cell line (MCF-7). The effects of this functionalized epoxide on cell proliferation (Ki67 staining), cell necrosis (propidium iodide staining), as well as the analysis of the nuclear area and near neighbor distance in MCF-7 cells, were analyzed. From this set of biological studies, strong evidence of the activation of apoptosis was found. In contrast, no significant neuroprotection against 6-OHDA-induced neurotoxicity was observed for the less cytotoxic steroids in N27 cells. Lastly, molecular docking simulations were achieved to verify the potential affinity of these compounds against important targets of steroidal drugs (androgen receptor, estrogen receptor \u03b1, and 5\u03b1-reductase type 2, 17\u03b1-hydroxylase-17,20-lyase and aromatase enzymes). This in silico study predicted a strong affinity between most novel steroidal derivatives and 5\u03b1-reductase and 17\u03b1-hydroxylase-17,20-lyase enzymes.<\/jats:p>","DOI":"10.3390\/biomedicines11030812","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T03:29:05Z","timestamp":1678246145000},"page":"812","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis, In Vitro Biological Evaluation of Antiproliferative and Neuroprotective Effects and In Silico Studies of Novel 16E-Arylidene-5\u03b1,6\u03b1-epoxyepiandrosterone Derivatives"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8030-9379","authenticated-orcid":false,"given":"Vanessa","family":"Brito","sequence":"first","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Mariana","family":"Marques","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Marta","family":"Esteves","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8606-7630","authenticated-orcid":false,"given":"Catarina","family":"Serra-Almeida","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4213-0714","authenticated-orcid":false,"given":"Gilberto","family":"Alves","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0110-4795","authenticated-orcid":false,"given":"Paulo","family":"Almeida","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Liliana","family":"Bernardino","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4297-5108","authenticated-orcid":false,"given":"Samuel","family":"Silvestre","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, 3004-517 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,7]]},"reference":[{"key":"ref_1","unstructured":"Burger, A., Abraham, D.J., and Rotella, D.P. (2010). 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