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This study evaluated the cytotoxic and proteasome inhibitory activities of 12R-hydroxy-bromosphaerol, 12S-hydroxy-bromosphaerol, and bromosphaerol isolated from Sphaerococcus coronopifolius. The cytotoxicity was evaluated on malignant cell lines (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, and SK-MEL-28) using the MTT and LDH assays. The ability of compounds to stimulate the production of hydrogen peroxide (H2O2) and to induce mitochondrial dysfunction, the externalization of phosphatidylserine, Caspase-9 activity, and changes in nuclear morphology was also studied on MCF-7 cells. The ability to induce DNA damage was also studied on L929 fibroblasts. The proteasome inhibitory activity was estimated through molecular docking studies. The compounds exhibited IC50 values between 15.35 and 53.34 \u00b5M. 12R-hydroxy-bromosphaerol and 12S-hydroxy-bromosphaerol increased the H2O2 levels on MCF-7 cells, and bromosphaerol induced DNA damage on fibroblasts. All compounds promoted a depolarization of mitochondrial membrane potential, Caspase-9 activity, and nuclear condensation and fragmentation. The compounds have been shown to interact with the chymotrypsin-like catalytic site through molecular docking studies; however, only 12S-hydroxy-bromosphaerol evidenced interaction with ALA20 and SER169, key residues of the proteasome catalytic mechanism. Further studies should be outlined to deeply characterize and understand the potential of those bromoditerpenes for anticancer therapeutics.<\/jats:p>","DOI":"10.3390\/md20100652","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T22:49:46Z","timestamp":1666306186000},"page":"652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bromoditerpenes from the Red Seaweed Sphaerococcus coronopifolius as Potential Cytotoxic Agents and Proteasome Inhibitors and Related Mechanisms of Action"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1581-2127","authenticated-orcid":false,"given":"Celso","family":"Alves","sequence":"first","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre, ARNET\u2014Aquatic Research Network, Polit\u00e9cnico de Leiria, 2520-630 Peniche, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-1699","authenticated-orcid":false,"given":"Joana","family":"Silva","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre, ARNET\u2014Aquatic Research Network, Polit\u00e9cnico de Leiria, 2520-630 Peniche, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3290-3111","authenticated-orcid":false,"given":"Susete","family":"Pint\u00e9us","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre, ARNET\u2014Aquatic Research Network, Polit\u00e9cnico de Leiria, 2520-630 Peniche, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4397-7968","authenticated-orcid":false,"given":"Romina A.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-9181","authenticated-orcid":false,"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8796-1389","authenticated-orcid":false,"given":"Rebeca","family":"Alvari\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, 27002 Lugo, Spain"}]},{"given":"Rafaela","family":"Freitas","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre, ARNET\u2014Aquatic Research Network, Polit\u00e9cnico de Leiria, 2520-630 Peniche, Portugal"}]},{"given":"M\u00e1rcia I.","family":"Goettert","sequence":"additional","affiliation":[{"name":"Cell Culture Laboratory, Postgraduate Programme in Biotechnology, University of Vale do Taquari\u2014Univates, CEP 95914-014 Lajeado, RS, Brazil"},{"name":"Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls Universit\u00e4t T\u00fcbingen, 72074 T\u00fcbingen, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-7023","authenticated-orcid":false,"given":"Helena","family":"Gaspar","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculty of Science, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1572-9016","authenticated-orcid":false,"given":"Amparo","family":"Alfonso","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, 27002 Lugo, Spain"}]},{"given":"Maria C.","family":"Alpo\u00edm","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-517 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2153-6608","authenticated-orcid":false,"given":"Luis M.","family":"Botana","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, 27002 Lugo, Spain"}]},{"given":"Rui","family":"Pedrosa","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre, ARNET\u2014Aquatic Research Network, ESTM, Polit\u00e9cnico de Leiria, 2520-614 Peniche, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1021\/acs.jcim.8b00125","article-title":"Cheminformatic Insight into the Differences between Terrestrial and Marine Originated Natural Products","volume":"58","author":"Shang","year":"2018","journal-title":"J. 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