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In the present study, esterase\u2010activatable fluorogenic prodrugs of the chemotherapeutic drug 5\u2010fluorouracil (<jats:bold>5\u2010FU<\/jats:bold>) have been rationally designed and synthesized using multi\u2010step organic synthesis. While <jats:bold>5\u2010FU<\/jats:bold> was connected directly with the fluorophore via a C\u2212N bond in the prodrug <jats:bold>BJ\u201050<\/jats:bold>, an additional self\u2010immolative benzylic spacer with a carbonate linker was incorporated in the prodrug <jats:bold>BJ\u201092<\/jats:bold>. Although absorption and emission spectroscopic studies revealed the activation of both the prodrugs by porcine liver esterase (PLE), reverse\u2010phase HPLC studies confirmed the inability of <jats:bold>BJ\u201050<\/jats:bold> to release the active drug <jats:bold>5\u2010FU<\/jats:bold>. In contrast, a sustained release of <jats:bold>5\u2010FU<\/jats:bold> and <jats:bold>Cou\u2010OH<\/jats:bold> was observed from <jats:bold>BJ\u201092<\/jats:bold> in the presence of PLE. The endogenous esterase\u2010mediated activation of the prodrug <jats:bold>BJ\u201092<\/jats:bold> was validated by the turn\u2010on fluorescence in A549 cells and the anti\u2010proliferative activities in A549, and HEK\u2010293 cells. Modulation of the expression of a few cancer marker proteins by <jats:bold>BJ\u201092<\/jats:bold> and <jats:bold>5\u2010FU<\/jats:bold> was studied to evaluate their anticancer activities. As esterases are overexpressed in cancer cells, the prodrug in the present study would be helpful in selectively delivering <jats:bold>5\u2010FU<\/jats:bold> to cancer cells with reduced off\u2010target side\u2010effects.<\/jats:p>","DOI":"10.1002\/asia.202400846","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T08:08:04Z","timestamp":1730448484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Esterase\u2010Responsive Self\u2010Immolative Prodrugs for the Sustained Delivery of the Anticancer Drug 5\u2010Fluorouracil with Turn\u2010On Fluorescence"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-054X","authenticated-orcid":false,"given":"Md","family":"Badirujjaman","sequence":"first","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Guwahati  Guwahati, Assam 781039 India"},{"name":"Department of Biosciences and Bioengineering Indian Institute of Technology Guwahati  Guwahati, Assam 781039 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-8364","authenticated-orcid":false,"given":"Rajkumar P.","family":"Thummer","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioengineering Indian Institute of Technology Guwahati  Guwahati, Assam 781039 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9115-7561","authenticated-orcid":false,"given":"Krishna P.","family":"Bhabak","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Guwahati  Guwahati, Assam 781039 India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21708"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2018.04.027"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/1078155219877931"},{"key":"e_1_2_9_5_1","unstructured":"\u00a0"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/179663a0"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2015.1022062"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1074"},{"key":"e_1_2_9_9_1","unstructured":"\u00a0"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.8b00539"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.107447"},{"key":"e_1_2_9_12_1","first-page":"33","volume":"13","author":"Macdonald J. 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