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Most derivatives demonstrated enhanced antiproliferative activity compared to that of carnosic acid 1. The most promising derivatives were tested in other colorectal cancer cell lines (SW480, SW620, and Caco-2), melanoma (A375), and pancreatic cancer (MiaPaca-2). Derivative 14 consistently demonstrated the highest activity across all tested cancer cell lines, showing selectivity for cancer cells over normal cells. Further investigation of the mechanism of action in SW480 cells revealed that compound 14 induced cell cycle arrest at the G0\/G1 phase by downregulating CDK4 and CDK6. Molecular docking studies revealed that compound 14 established several interactions with key residues in the active site of CDK6. Additionally, compound 14 also reduced ROS production. In summary, our results strongly indicate that compound 14 has potential as a lead compound in the development of innovative anticancer drugs.<\/jats:p>","DOI":"10.3390\/ijms252413332","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T06:29:30Z","timestamp":1733984970000},"page":"13332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Design, Synthesis, and Biological Evaluation of Novel Urea-Containing Carnosic Acid Derivatives with Anticancer Activity"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5791-6528","authenticated-orcid":false,"given":"Sara P. S. P.","family":"Moura","sequence":"first","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0693-2207","authenticated-orcid":false,"given":"Silvia","family":"Mar\u00edn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3718-3264","authenticated-orcid":false,"given":"Ismael","family":"Rufino","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisboa, 1649-003 Lisboa, 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, University of Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2062-4633","authenticated-orcid":false,"given":"Marta","family":"Cascante","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0779-6083","authenticated-orcid":false,"given":"Jorge A. R.","family":"Salvador","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA-Cancer J. 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