{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T07:55:26Z","timestamp":1770278126621,"version":"3.49.0"},"reference-count":57,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2012,7,16]],"date-time":"2012-07-16T00:00:00Z","timestamp":1342396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A series of ursolic acid ((1<jats:italic>S<\/jats:italic>,2<jats:italic>R<\/jats:italic>,4a<jats:italic>S<\/jats:italic>,6a<jats:italic>R<\/jats:italic>,6a<jats:italic>S<\/jats:italic>,6b<jats:italic>R<\/jats:italic>,8a<jats:italic>R<\/jats:italic>,10<jats:italic>S<\/jats:italic>,12a<jats:italic>R<\/jats:italic>,14b<jats:italic>S<\/jats:italic>)\u201010\u2010hydroxy\u20101,2,6a,6b,9,9,12a\u2010heptamethyl\u20102,3,4,5,6,6a,7,8,8a,10,11,12,13,14b\u2010tetradecahydro\u20101<jats:italic>H<\/jats:italic>\u2010picene\u20104a\u2010carboxylic acid) derivatives with a 12\u2010fluoro\u201013,28\u03b2\u2010lactone moiety were synthesized using the electrophilic fluorination reagent Selectfluor. The antiproliferative effects of these novel compounds were evaluated in AsPC\u20101 pancreatic cancer cells, and the structure\u2013activity relationships (SARs) were evaluated. Of the compounds synthesized, ursolic acid derivatives carrying a heterocyclic ring, such as imidazole or methylimidazole, and cyanoenones were among the more potent inhibitors of AsPC\u20101 pancreatic cancer cell growth. 2\u2010Cyano\u20103\u2010oxo\u201012\u03b1\u2010fluoro\u2010urs\u20101\u2010en\u201013,28\u03b2\u2010olide, compound <jats:bold>20<\/jats:bold>, was the most effective inhibitor with IC<jats:sub>50<\/jats:sub> values of 0.7, 0.9 and 1.8\u2005\u03bc<jats:sc>M<\/jats:sc> in pancreatic cancer cell lines AsPC\u20101, MIA PaCa\u20102 and PANC\u20101, respectively. This compound also exhibited better antiproliferative activities against breast (MCF7), prostate (PC\u20103), hepatocellular (Hep G2) and lung (A549) cancer cell lines, with IC<jats:sub>50<\/jats:sub> values lower than 1\u2005\u03bc<jats:sc>M<\/jats:sc>. The mechanism of action by which these compounds exert their biological effect was evaluated in AsPC\u20101 cells using the most potent inhibitor synthesized, compound <jats:bold>20<\/jats:bold>. At 1\u2005\u03bc<jats:sc>M<\/jats:sc>, the cell cycle arrested at the G1 phase with upregulation of p21<jats:sup>waf1<\/jats:sup>. Apoptosis was induced at an inhibitor concentration of 8\u2005\u03bc<jats:sc>M<\/jats:sc> with upregulation of NOXA and downregulation of c\u2010FLIP. These data indicate that fluorolactone derivatives of ursolic acid have improved antiproliferative activity, acting through arrest of the cell cycle and induction of apoptosis.<\/jats:p>","DOI":"10.1002\/cmdc.201200282","type":"journal-article","created":{"date-parts":[[2012,7,19]],"date-time":"2012-07-19T02:38:57Z","timestamp":1342665537000},"page":"1635-1646","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Semisynthetic Ursolic Acid Fluorolactone Derivatives Inhibit Growth with Induction of p21<sup>waf1<\/sup> and Induce Apoptosis with Upregulation of NOXA and Downregulation of c\u2010FLIP in Cancer Cells"],"prefix":"10.1002","volume":"7","author":[{"given":"Ana S.","family":"Leal","sequence":"first","affiliation":[]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Jorge A. 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