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Cyclic enones, both from natural sources and synthetic analogues, have been described as cytotoxic agents. Most of these agents were unsuccessful in becoming valuable therapeutic agents due to toxicity problems derived from unselective critical biomacromolecule alkylation. This may be caused by Michael addition to the enone system. <jats:italic>Ab initio<\/jats:italic> studies revealed that 2,4\u2010substituted CPs are less prone to Michael additions, and as such were tested three families of those derivatives. We prepare the new CPs from furfural through a tandem furan ring opening\/Nazarov electrocyclization and further functionalization. Experimentally the 2,4\u2010substituted CPs exhibited no reactivity towards sulphur nucleophiles, while maintaining cytotoxicity against HT\u201029, MCF\u20107, NCI\u2010H460, HCT\u2010116 and MDA\u2010MB 231 cells lines. Moreover, the selected CP are non\u2010toxic against healthy HEK 293T cell lines and present proper calculated drug\u2010like properties.<\/jats:p>","DOI":"10.1002\/cmdc.202300104","type":"journal-article","created":{"date-parts":[[2023,4,16]],"date-time":"2023-04-16T22:09:05Z","timestamp":1681682945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functionalized Cyclopentenones with Low Electrophilic Character as Anticancer Agents"],"prefix":"10.1002","volume":"18","author":[{"given":"K\u00e9ssia H. S.","family":"Andrade","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  1649-003 Lisboa Portugal"}]},{"given":"Jaime A. 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Babraham Research Campus  Cambridge CB22 3AT UK"},{"name":"Department of Chemistry University College London  London WC1H 0AJ UK"}]},{"given":"Stephen","family":"Caddick","sequence":"additional","affiliation":[{"name":"Department of Chemistry University College London  London WC1H 0AJ UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2598-8540","authenticated-orcid":false,"given":"Rafael F. A.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  1649-003 Lisboa Portugal"},{"name":"CBIOS-Universidade Lus\u00f3fona's Research Center for Biosciences &amp; Health Technologies Universidade Lus\u00f3fona, Lisboa  1749-024 Lisboa Portugal"}]},{"given":"Carlos A. 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