{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:00:13Z","timestamp":1792699213073,"version":"4.5.0"},"reference-count":181,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100024370","name":"Governo Italiano Ministero dell&apos;Istruzione dell&apos;Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["E53D23015960001"],"award-info":[{"award-number":["E53D23015960001"]}],"id":[{"id":"10.13039\/501100024370","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1016\/j.ejmech.2026.118967","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:48:30Z","timestamp":1779205710000},"page":"118967","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Beyond conventional 5-Fluorouracil: Recent medicinal chemistry strategies to enhance its anticancer efficacy"],"prefix":"10.1016","volume":"315","author":[{"given":"Sara","family":"Mocka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria N.","family":"Modica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Pittal\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"Salerno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Romeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Marrazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Siracusa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-1745","authenticated-orcid":false,"given":"Sebastiano","family":"Intagliata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejmech.2026.118967_bib1","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1517\/13543776.2015.1056736","article-title":"5-Fluorouracil derivatives: a patent review (2012 \u2013 2014)","volume":"25","author":"Carrillo","year":"2015","journal-title":"Expert Opin. Ther. Pat."},{"key":"10.1016\/j.ejmech.2026.118967_bib2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2174\/1389201003378979","article-title":"The history, mechanism and clinical use of oral 5-Fluorouracil derivative chemotherapeutic agents","volume":"1","author":"Tanaka","year":"2000","journal-title":"Curr. Pharm. Biotechnol."},{"key":"10.1016\/j.ejmech.2026.118967_bib3","doi-asserted-by":"crossref","first-page":"5445","DOI":"10.2147\/IJN.S257700","article-title":"Recent advances in designing 5-Fluorouracil delivery systems: a stepping stone in the safe treatment of colorectal cancer","volume":"15","author":"Entezar-Almahdi","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"10.1016\/j.ejmech.2026.118967_bib4","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/ardp.200900075","article-title":"Synthesis and characterization of new liver targeting 5-Fluorouracil-Cholic acid conjugates","volume":"342","author":"Qian","year":"2009","journal-title":"Arch. Pharm."},{"key":"10.1016\/j.ejmech.2026.118967_bib5","first-page":"119","article-title":"Studies in 2-Acetylaminofluorene carcinogenesis. III. The utilization of Uracil-2-C14 by preneoplastic Rat liver and rat hepatoma","volume":"14","author":"Rutman","year":"1954","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib6","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/annonc\/mdm285","article-title":"Effective oral chemotherapy for breast cancer: pillars of strength","volume":"19","author":"Findlay","year":"2008","journal-title":"Ann. Oncol."},{"key":"10.1016\/j.ejmech.2026.118967_bib7","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1002\/cmdc.202100473","article-title":"Mutual prodrugs of 5-Fluorouracil: from a classic chemotherapeutic agent to novel potential anticancer drugs","volume":"16","author":"Ciaffaglione","year":"2021","journal-title":"ChemMedChem"},{"key":"10.1016\/j.ejmech.2026.118967_bib8","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nrc1074","article-title":"5-Fluorouracil: mechanisms of action and clinical strategies","volume":"3","author":"Longley","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.ejmech.2026.118967_bib9","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3390\/pharmaceutics11050199","article-title":"DPYD and fluorouracil-based chemotherapy: mini review and case report","volume":"11","author":"Wigle","year":"2019","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.ejmech.2026.118967_bib10","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/jcp.1041040305","article-title":"Facilitated transport of uracil and 5-Fluorouracil, and permeation of orotic acid into cultured mammalian cells","volume":"104","author":"Wohlhueter","year":"1980","journal-title":"J. Cell. Physiol."},{"key":"10.1016\/j.ejmech.2026.118967_bib11","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jpha.2020.04.001","article-title":"Study of intracellular anabolism of 5-Fluorouracil and incorporation in nucleic acids based on an LC-HRMS method","volume":"11","author":"Machon","year":"2021","journal-title":"J. Pharm. Anal."},{"key":"10.1016\/j.ejmech.2026.118967_bib12","series-title":"Enzyme Active Sites and Their Reaction Mechanisms","first-page":"225","article-title":"Chapter 37 - thymidylate synthase","author":"Morrison","year":"2021"},{"key":"10.1016\/j.ejmech.2026.118967_bib13","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.3390\/cancers2031717","article-title":"5-FU metabolism in cancer and orally-administrable 5-FU drugs","volume":"2","author":"Miura","year":"2010","journal-title":"Cancers"},{"key":"10.1016\/j.ejmech.2026.118967_bib14","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1073\/pnas.69.7.1855","article-title":"5-Fluoro-2\u2032-Deoxyuridylate: covalent complex with thymidylate synthetase","volume":"69","author":"Santi","year":"1972","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"10.1016\/j.ejmech.2026.118967_bib15","doi-asserted-by":"crossref","first-page":"8235","DOI":"10.1016\/S0021-9258(18)47554-0","article-title":"Deoxyribonucleoside triphosphate imbalance. 5-Fluorodeoxyuridine-Induced DNA double strand breaks in mouse FM3A cells and the mechanism of cell death","volume":"262","author":"Yoshioka","year":"1987","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2023.115902","article-title":"The relationship between tumor metabolism and 5-Fluorouracil resistance","volume":"218","author":"Hu","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.118967_bib17","doi-asserted-by":"crossref","first-page":"6139","DOI":"10.1093\/nar\/19.22.6139","article-title":"Interactions of transfer RNA pseudouridine synthases with RNAs substituted with fluorouracil","volume":"19","author":"Samuelsson","year":"1991","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib18","series-title":"Antineoplastic and Immunosuppressive Agents: Part II","first-page":"193","article-title":"Fluorinated pyrimidines and their nucleosides","author":"Heidelberger","year":"1975"},{"key":"10.1016\/j.ejmech.2026.118967_bib19","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1021\/acsptsci.2c00117","article-title":"Dihydropyrimidine dehydrogenase-mediated resistance to 5-Fluorouracil: Mechanistic investigation and solution","volume":"5","author":"Verma","year":"2022","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib20","doi-asserted-by":"crossref","unstructured":"Launay, M.; Ciccolini, J.; Rodallec, A.; Fournel, C.; Duffaud, F.; Salas, S.; Lacarelle, B. Upfront DPD deficiency detection to secure 5-FU administration: part 1 \u2013 where do we stand? Clin. Cancer Drugs 4, 74\u201381, doi:10.2174\/2212697X04666170531080625.","DOI":"10.2174\/2212697X04666170531080625"},{"key":"10.1016\/j.ejmech.2026.118967_bib21","doi-asserted-by":"crossref","first-page":"567","DOI":"10.2165\/00003088-200645060-00002","article-title":"How may anticancer chemotherapy with fluorouracil be individualised?","volume":"45","author":"Ploylearmsaeng","year":"2006","journal-title":"Clin. Pharmacokinet."},{"key":"10.1016\/j.ejmech.2026.118967_bib22","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1517\/13543780902729412","article-title":"S-1: a promising new oral fluoropyrimidine derivative","volume":"18","author":"Saif","year":"2009","journal-title":"Expert Opin. Invest. Drugs"},{"key":"10.1016\/j.ejmech.2026.118967_bib23","first-page":"2203","article-title":"Clinical pharmacokinetics of 5-Fluorouracil and its metabolites in plasma, urine, and bile","volume":"47","author":"Heggie","year":"1987","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib24","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/BF00662639","article-title":"Experimental neurotoxicity of 5-Fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and \u03b1-Fluoro-\u03b2-Alanine","volume":"81","author":"Okeda","year":"1990","journal-title":"Acta Neuropathol."},{"key":"10.1016\/j.ejmech.2026.118967_bib25","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/S0021-5198(19)52945-6","article-title":"Cardiotoxic effects of 5-Fluorouracil in the Guinea pig","volume":"30","author":"Matsubara","year":"1980","journal-title":"Jpn. J. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.118967_bib26","doi-asserted-by":"crossref","first-page":"4759","DOI":"10.1016\/0006-2952(88)90349-8","article-title":"Circadian rhythm of rat liver dihydropyrimidine dehydrogenase: possible relevance to fluoropyrimidine chemotherapy","volume":"37","author":"Harris","year":"1988","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.118967_bib27","first-page":"197","article-title":"Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-Fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-Fluorouracil by protracted continuous infusion","volume":"50","author":"Harris","year":"1990","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib28","doi-asserted-by":"crossref","DOI":"10.1016\/j.pharmthera.2019.107447","article-title":"5-Fluorouracil and other fluoropyrimidines in colorectal cancer: past, present and future","volume":"206","author":"Vodenkova","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"10.1016\/j.ejmech.2026.118967_bib29","first-page":"2223","article-title":"Pharmacokinetics of 5-Fluorouracil administered orally by rapid intravenous and by slow infusion","volume":"40","author":"Fraile","year":"1980","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib30","first-page":"79","article-title":"Capecitabine in the management of colorectal cancer","volume":"3","author":"Hirsch","year":"2011","journal-title":"Cancer Manag. Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib31","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.3390\/molecules13102340","article-title":"Novel strategies to improve the anticancer action of 5-Fluorouracil by using drug delivery systems","volume":"13","author":"Arias","year":"2008","journal-title":"Molecules"},{"key":"10.1016\/j.ejmech.2026.118967_bib32","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1080\/17425247.2017.1316260","article-title":"Drug delivery of oral anti-cancer fluoropyrimidine agents","volume":"14","author":"Miura","year":"2017","journal-title":"Expert Opin. Drug Deliv."},{"key":"10.1016\/j.ejmech.2026.118967_bib33","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1517\/13543776.2012.661413","article-title":"5-Fluorouracil derivatives: a patent review","volume":"22","author":"\u00c1lvarez","year":"2012","journal-title":"Expert Opin. Ther. Pat."},{"key":"10.1016\/j.ejmech.2026.118967_bib34","first-page":"48","article-title":"The oral fluorouracil prodrugs","volume":"12","author":"Pazdur","year":"1998","journal-title":"Oncology"},{"key":"10.1016\/j.ejmech.2026.118967_bib35","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1007\/s005950070003","article-title":"A phase II trial of a new 5-Fluorouracil derivative, BOF-A2 (emitefur), for patients with advanced gastric cancer","volume":"30","author":"Sugimachi","year":"2000","journal-title":"Surg. Today"},{"key":"10.1016\/j.ejmech.2026.118967_bib36","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1039\/C6BM00884D","article-title":"A rapid albumin-binding 5-Fluorouracil prodrug with a prolonged circulation time and enhanced antitumor activity","volume":"5","author":"Zhao","year":"2017","journal-title":"Biomater. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib37","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1158\/0008-5472.CAN-09-3690","article-title":"5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity","volume":"70","author":"Vincent","year":"2010","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib38","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/nrclinonc.2010.223","article-title":"Immune parameters affecting the efficacy of chemotherapeutic regimens","volume":"8","author":"Zitvogel","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"10.1016\/j.ejmech.2026.118967_bib39","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41571-020-0413-z","article-title":"Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors","volume":"17","author":"Galluzzi","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"10.1016\/j.ejmech.2026.118967_bib40","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s00280-023-04528-5","article-title":"The novel anti-cancer fluoropyrimidine NUC-3373 is a potent inhibitor of thymidylate synthase and an effective DNA-Damaging agent","volume":"91","author":"Br\u00e9","year":"2023","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.118967_bib41","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1200\/JCO.2021.39.3_suppl.93","article-title":"A phase Ib Study of NUC-3373 in combination with standard therapies in Advanced\/Metastatic colorectal cancer (NuTide:302)","volume":"39","author":"Coveler","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.ejmech.2026.118967_bib42","article-title":"A phase Ib\/II multi-arm, dose finding and expansion study of a novel thymidylate synthase inhibitor with immune modulating properties, NUC-3373","volume":"vol 303","author":"Middleton","year":"2025"},{"key":"10.1016\/j.ejmech.2026.118967_bib43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1734-1140(13)70959-9","article-title":"Prodrugs: a challenge for the drug development","volume":"65","author":"Zawilska","year":"2013","journal-title":"Pharmacol. Rep."},{"key":"10.1016\/j.ejmech.2026.118967_bib44","doi-asserted-by":"crossref","first-page":"14379","DOI":"10.1021\/acs.chemrev.6b00209","article-title":"Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogs","volume":"116","author":"Shelton","year":"2016","journal-title":"Chem. Rev."},{"key":"10.1016\/j.ejmech.2026.118967_bib45","series-title":"Design of Hybrid Molecules for Drug Development","author":"Decker","year":"2017"},{"key":"10.1016\/j.ejmech.2026.118967_bib46","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s42004-025-01491-5","article-title":"Towards precision medicine using biochemically triggered cleavable conjugation","volume":"8","author":"Parshad","year":"2025","journal-title":"Commun. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib47","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2022.114995","article-title":"5-Fluorouracil nano-delivery systems as a cutting-edge for cancer therapy","volume":"246","author":"Valencia-Lazcano","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib48","doi-asserted-by":"crossref","first-page":"966","DOI":"10.3390\/pharmaceutics16070966","article-title":"Stimuli-responsive liposomes of 5-Fluorouracil: progressive steps for safe and effective treatment of colorectal cancer","volume":"16","author":"Alrbyawi","year":"2024","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.ejmech.2026.118967_bib49","doi-asserted-by":"crossref","first-page":"734","DOI":"10.3390\/pharmaceutics16060734","article-title":"Review of prodrug and nanodelivery strategies to improve the treatment of colorectal cancer with fluoropyrimidine drugs","volume":"16","author":"Sarkar","year":"2024","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.ejmech.2026.118967_bib50","doi-asserted-by":"crossref","unstructured":"Cardona-G, W.; Herrera-R, A.; Castrill\u00f3n-L, W.; Ram\u00edrez-Malule, H. Chemistry and anticancer activity of hybrid molecules and derivatives based on 5-Fluorouracil. Curr. Med. Chem. 28, 5551\u20135601, doi:10.2174\/0929867328666210211164314.","DOI":"10.2174\/0929867328666210211164314"},{"key":"10.1016\/j.ejmech.2026.118967_bib51","doi-asserted-by":"crossref","first-page":"4655","DOI":"10.21873\/anticanres.14464","article-title":"Current status of therapeutic drug monitoring of 5-Fluorouracil prodrugs","volume":"40","author":"Hashimoto","year":"2020","journal-title":"Anticancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib52","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3892\/or.2023.8612","article-title":"5-Fluorouracil and capecitabine therapies for the treatment of colorectal cancer","volume":"50","author":"Alzahrani","year":"2023","journal-title":"Oncol. Rep."},{"key":"10.1016\/j.ejmech.2026.118967_bib53","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.cbpa.2020.10.001","article-title":"Transition metal catalysts for the bioorthogonal synthesis of bioactive agents","volume":"61","author":"van de L'Isle","year":"2021","journal-title":"Curr. Opin. Chem. Biol."},{"key":"10.1016\/j.ejmech.2026.118967_bib54","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1021\/acscentsci.1c00124","article-title":"Unleashing the power of bond cleavage chemistry in living systems","volume":"7","author":"Wang","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib55","doi-asserted-by":"crossref","first-page":"7354","DOI":"10.1039\/C8SC02291G","article-title":"Bright insights into palladium-triggered local chemotherapy","volume":"9","author":"Bray","year":"2018","journal-title":"Chem. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib56","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1021\/acs.jmedchem.1c01733","article-title":"A 5-FU precursor designed to evade anabolic and catabolic drug pathways and activated by Pd chemistry in vitro and in vivo","volume":"65","author":"Adam","year":"2022","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib57","doi-asserted-by":"crossref","first-page":"3277","DOI":"10.1038\/ncomms4277","article-title":"Extracellular palladium-catalysed dealkylation of 5-Fluoro-1-Propargyl-Uracil as a bioorthogonally activated prodrug approach","volume":"5","author":"Weiss","year":"2014","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejmech.2026.118967_bib58","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The warburg effect: how does it benefit cancer cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib59","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ccr.2006.10.020","article-title":"A Mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth","volume":"11","author":"Bonnet","year":"2007","journal-title":"Cancer Cell"},{"key":"10.1016\/j.ejmech.2026.118967_bib60","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.pharmthera.2016.10.018","article-title":"Therapeutic applications of dichloroacetate and the role of glutathione transferase Zeta-1","volume":"170","author":"James","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"10.1016\/j.ejmech.2026.118967_bib61","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1542\/peds.2005-1226","article-title":"Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children","volume":"117","author":"Stacpoole","year":"2006","journal-title":"Pediatrics"},{"key":"10.1016\/j.ejmech.2026.118967_bib62","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-31797-5","article-title":"Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells","volume":"8","author":"Florio","year":"2018","journal-title":"Sci. Rep."},{"key":"10.1016\/j.ejmech.2026.118967_bib63","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2023.106784","article-title":"Development of 5-Fluorouracil-Dichloroacetate mutual prodrugs as anticancer agents","volume":"140","author":"Mironiuk-Puchalska","year":"2023","journal-title":"Bioorg. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib64","doi-asserted-by":"crossref","first-page":"524","DOI":"10.3389\/fphar.2020.00524","article-title":"Advances in oral drug delivery for regional targeting in the gastrointestinal tract - influence of physiological, pathophysiological and pharmaceutical factors","volume":"11","author":"Hua","year":"2020","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.118967_bib65","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.7150\/ijbs.44943","article-title":"Mechanical tumor microenvironment and transduction: Cytoskeleton mediates cancer cell invasion and metastasis","volume":"16","author":"Li","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib66","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41571-020-0339-5","article-title":"Exploiting the folate receptor \u03b1 in oncology","volume":"17","author":"Scaranti","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"10.1016\/j.ejmech.2026.118967_bib67","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1002\/cmdc.200800125","article-title":"Targeting the folate Receptor (FR): imaging and cytotoxicity of ReI conjugates in FR-Overexpressing cancer cells","volume":"3","author":"Viola-Villegas","year":"2008","journal-title":"ChemMedChem"},{"key":"10.1016\/j.ejmech.2026.118967_bib68","doi-asserted-by":"crossref","first-page":"21750","DOI":"10.3390\/molecules201219804","article-title":"Polymer-based prodrugs: improving tumor targeting and the solubility of small molecule drugs in cancer therapy","volume":"20","author":"Dragojevic","year":"2015","journal-title":"Molecules"},{"key":"10.1016\/j.ejmech.2026.118967_bib69","first-page":"1780","article-title":"Folate conjugated polyethylene glycol probe for tumor-targeted drug delivery of 5-Fluorouracil","volume":"27","author":"Sarwar","year":"2022","journal-title":"Mol. Basel Switz."},{"key":"10.1016\/j.ejmech.2026.118967_bib70","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41573-018-0005-0","article-title":"Polymer\u2013drug conjugate therapeutics: advances, insights and prospects","volume":"18","author":"Ekladious","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"10.1016\/j.ejmech.2026.118967_bib71","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.carbpol.2019.05.067","article-title":"Review of polysaccharide particle-based functional drug delivery","volume":"221","author":"Barclay","year":"2019","journal-title":"Carbohydr. Polym."},{"key":"10.1016\/j.ejmech.2026.118967_bib72","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.biomaterials.2015.03.021","article-title":"Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic","volume":"54","author":"Xu","year":"2015","journal-title":"Biomaterials"},{"key":"10.1016\/j.ejmech.2026.118967_bib73","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.ijpharm.2016.07.025","article-title":"Paclitaxel-loaded chitosan oligosaccharide-stabilized gold nanoparticles as novel agents for drug delivery and photoacoustic imaging of cancer cells","volume":"511","author":"Manivasagan","year":"2016","journal-title":"Int. J. Pharm."},{"key":"10.1016\/j.ejmech.2026.118967_bib74","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.biopha.2016.10.004","article-title":"Colon cancer targeting using conjugates biomaterial 5-Flurouracil","volume":"84","author":"Jaferian","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"10.1016\/j.ejmech.2026.118967_bib75","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1111\/cbdd.14298","article-title":"Structural properties and immune-enhancing activities of galactan isolated from red seaweed Grateloupia filicina","volume":"102","author":"Ma","year":"2023","journal-title":"Chem. Biol. Drug Des."},{"key":"10.1016\/j.ejmech.2026.118967_bib76","first-page":"181","article-title":"Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-Fluorouracil administration","volume":"4","author":"Ezzeldin","year":"2004","journal-title":"Clin. Colorectal Cancer"},{"key":"10.1016\/j.ejmech.2026.118967_bib77","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1007\/s00280-011-1709-6","article-title":"Severe fluoropyrimidine-related toxicity: clinical implications of DPYD analysis and UH2\/U ratio evaluation","volume":"68","author":"Giorgio","year":"2011","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.118967_bib78","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1021\/mp070050b","article-title":"Folate-targeted dinitrophenyl hapten immunotherapy: effect of linker chemistry on antitumor activity and allergic potential","volume":"4","author":"Lu","year":"2007","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.ejmech.2026.118967_bib79","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.ab.2004.12.026","article-title":"Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay","volume":"338","author":"Parker","year":"2005","journal-title":"Anal. Biochem."},{"key":"10.1016\/j.ejmech.2026.118967_bib80","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.cbpa.2009.03.022","article-title":"Folate-targeted therapeutic and imaging agents for cancer","volume":"13","author":"Low","year":"2009","journal-title":"Curr. Opin. Chem. Biol."},{"key":"10.1016\/j.ejmech.2026.118967_bib81","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijbiomac.2024.133121","article-title":"Preparation of novel sulfated Polysaccharide-Carboxymethyl-5-Fluorouracil-Folic acid conjugates for targeted anticancer drug delivery","volume":"273","author":"Ma","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"10.1016\/j.ejmech.2026.118967_bib82","doi-asserted-by":"crossref","first-page":"6578","DOI":"10.1021\/nn202452c","article-title":"Selenium nanoparticles as a carrier of 5-Fluorouracil to achieve anticancer synergism","volume":"6","author":"Liu","year":"2012","journal-title":"ACS Nano"},{"key":"10.1016\/j.ejmech.2026.118967_bib83","doi-asserted-by":"crossref","first-page":"4155","DOI":"10.1021\/ja00274a051","article-title":"Crystal structure of methotrexate tetrahydrate","volume":"108","author":"Sutton","year":"1986","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.ejmech.2026.118967_bib84","doi-asserted-by":"crossref","first-page":"34650","DOI":"10.1021\/acsami.7b10027","article-title":"Methotrexate\u2013camptothecin prodrug nanoassemblies as a versatile nanoplatform for biomodal imaging-guided self-active targeted and synergistic chemotherapy","volume":"9","author":"Li","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"10.1016\/j.ejmech.2026.118967_bib85","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/0065-2571(94)90025-6","article-title":"The methotrexate story: a paradigm for development of cancer chemotherapeutic agents","volume":"34","author":"Huennekens","year":"1994","journal-title":"Adv. Enzym. Regul."},{"key":"10.1016\/j.ejmech.2026.118967_bib86","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1039\/D0TB00468E","article-title":"\u201cWatson\u2013Crick GC\u201d-inspired supramolecular nanodrug of methotrexate and 5-Fluorouracil for tumor microenvironment-activatable self-recognizing synergistic chemotherapy","volume":"8","author":"Chen","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"10.1016\/j.ejmech.2026.118967_bib87","first-page":"30","article-title":"5-Fluorouracil-Methotrexate conjugate enhances the efficacy of 5-Fluorouracil in colorectal cancer therapy","volume":"43","author":"Zhao","year":"2025","journal-title":"Invest. N. Drugs"},{"key":"10.1016\/j.ejmech.2026.118967_bib88","first-page":"589","article-title":"Utility of sulfobutyl ether \u03b2-Cyclodextrin inclusion complexes in drug delivery: a review","volume":"81","author":"Lewis","year":"2019","journal-title":"Indian J. Pharmaceut. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib89","first-page":"267","article-title":"The prodrugs of 5-Fluorouracil","volume":"2","author":"Malet-Martino","year":"2002","journal-title":"Curr. Med. Chem. Anti Cancer Agents"},{"key":"10.1016\/j.ejmech.2026.118967_bib90","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1039\/D2SC01003H","article-title":"Stimulus-responsive self-assembled prodrugs in cancer therapy","volume":"13","author":"Dong","year":"2022","journal-title":"Chem. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib91","doi-asserted-by":"crossref","first-page":"647","DOI":"10.3389\/fchem.2020.00647","article-title":"Enzyme-responsive nanoparticles for anti-tumor drug delivery","volume":"8","author":"Li","year":"2020","journal-title":"Front. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib92","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1080\/10717544.2019.1588424","article-title":"Application and design of esterase-responsive nanoparticles for cancer therapy","volume":"26","author":"Dong","year":"2019","journal-title":"Drug Deliv."},{"key":"10.1016\/j.ejmech.2026.118967_bib93","first-page":"416","article-title":"Tumor microenvironment responsive drug delivery systems","volume":"15","author":"He","year":"2020","journal-title":"Asian J. Pharm. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib94","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1111\/j.1743-7563.2012.01545.x","article-title":"Differentiating malignant colorectal tumor patients from benign colorectal tumor patients by assaying morning urinary arylsulfatase activity","volume":"8","author":"Niu","year":"2012","journal-title":"Asia Pac. J. Clin. Oncol."},{"key":"10.1016\/j.ejmech.2026.118967_bib95","doi-asserted-by":"crossref","DOI":"10.1002\/asia.202400846","article-title":"Esterase-responsive self-immolative prodrugs for the sustained delivery of the anticancer drug 5-Fluorouracil with Turn-On fluorescence","volume":"20","author":"Badirujjaman","year":"2025","journal-title":"Chem. Asian J."},{"key":"10.1016\/j.ejmech.2026.118967_bib96","doi-asserted-by":"crossref","first-page":"97","DOI":"10.37358\/RC.20.12.8390","article-title":"Synthesis and kinetic study of novel Coumarin- based mutual prodrug of 5-Fluorouracil and 5-Ethynyluracil","volume":"71","author":"Mustafa","year":"2021","journal-title":"Rev. Chim. (Bucharest, Rom.)"},{"key":"10.1016\/j.ejmech.2026.118967_bib97","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1021\/acs.biochem.1c00096","article-title":"The interaction of porcine dihydropyrimidine dehydrogenase with the chemotherapy sensitizer: 5-ethynyluracil","volume":"60","author":"Forouzesh","year":"2021","journal-title":"Biochemistry"},{"key":"10.1016\/j.ejmech.2026.118967_bib98","doi-asserted-by":"crossref","first-page":"5236","DOI":"10.1016\/S0021-9258(18)42757-3","article-title":"Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-Ethynyluracil","volume":"267","author":"Porter","year":"1992","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib99","doi-asserted-by":"crossref","DOI":"10.1016\/j.molstruc.2023.137415","article-title":"Triple coumarin-based 5-Fluorouracil prodrugs, their synthesis, characterization, and release kinetics","volume":"1301","author":"Mustafa","year":"2024","journal-title":"J. Mol. Struct."},{"key":"10.1016\/j.ejmech.2026.118967_bib100","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1515\/hsz-2019-0135","article-title":"Recent advances in the development of legumain-selective chemical probes and peptide prodrugs","volume":"400","author":"Poreba","year":"2019","journal-title":"Biol. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib101","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02174042","article-title":"Families and clans of cysteine peptidases","volume":"6","author":"Barrett","year":"1996","journal-title":"Perspect. Drug Discov. Des."},{"key":"10.1016\/j.ejmech.2026.118967_bib102","doi-asserted-by":"crossref","DOI":"10.3389\/fmolb.2023.1121964","article-title":"Role of LGMN in tumor development and its progression and connection with the tumor microenvironment","volume":"10","author":"Khan","year":"2023","journal-title":"Front. Mol. Biosci."},{"key":"10.1016\/j.ejmech.2026.118967_bib103","doi-asserted-by":"crossref","DOI":"10.1155\/2011\/740564","article-title":"Synergistic antitumor effect of dichloroacetate in combination with 5-Fluorouracil in colorectal cancer","volume":"2011","author":"Tong","year":"2011","journal-title":"BioMed Res. Int."},{"key":"10.1016\/j.ejmech.2026.118967_bib104","doi-asserted-by":"crossref","first-page":"257","DOI":"10.20517\/cdr.2022.136","article-title":"Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-Target effects","volume":"6","author":"Gmeiner","year":"2023","journal-title":"Cancer Drug Resist"},{"key":"10.1016\/j.ejmech.2026.118967_bib105","doi-asserted-by":"crossref","DOI":"10.1016\/j.molstruc.2023.136644","article-title":"Natural coumarins from two cultivars of watermelon seeds as biosafe anticancer agents, an algorithm for their isolation and evaluation","volume":"1295","author":"Mustafa","year":"2024","journal-title":"J. Mol. Struct."},{"key":"10.1016\/j.ejmech.2026.118967_bib106","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.identj.2022.08.003","article-title":"The use of trojan-horse drug delivery system in managing periodontitis","volume":"73","author":"G\u00e9czi","year":"2023","journal-title":"Int. Dent. J."},{"key":"10.1016\/j.ejmech.2026.118967_bib107","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41568-020-00308-y","article-title":"The rediscovery of platinum-based cancer therapy","volume":"21","author":"Rottenberg","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.ejmech.2026.118967_bib108","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.3390\/molecules27082466","article-title":"Application of approved cisplatin derivatives in combination therapy against different cancer diseases","volume":"27","author":"Tsvetkova","year":"2022","journal-title":"Molecules"},{"key":"10.1016\/j.ejmech.2026.118967_bib109","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1039\/b907567d","article-title":"Inhibition of transcription by platinum antitumor compounds","volume":"1","author":"Todd","year":"2009","journal-title":"Metallomics"},{"key":"10.1016\/j.ejmech.2026.118967_bib110","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ccr.2017.11.014","article-title":"Platinum coordination compounds with potent anticancer activity","volume":"375","author":"Deo","year":"2018","journal-title":"Coord. Chem. Rev."},{"key":"10.1016\/j.ejmech.2026.118967_bib111","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0010-8545(02)00026-7","article-title":"Platinum(IV) antitumour compounds: their bioinorganic chemistry","volume":"232","author":"Hall","year":"2002","journal-title":"Coord. Chem. Rev."},{"key":"10.1016\/j.ejmech.2026.118967_bib112","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1021\/jm070280u","article-title":"Basis for design and development of Platinum(IV) anticancer complexes","volume":"50","author":"Hall","year":"2007","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib113","doi-asserted-by":"crossref","first-page":"8757","DOI":"10.1021\/jm401218n","article-title":"Influence of equatorial and axial Carboxylato ligands on the kinetic inertness of Platinum(IV) complexes in the presence of ascorbate and Cysteine and within DLD-1 cancer cells","volume":"56","author":"Chen","year":"2013","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib114","doi-asserted-by":"crossref","first-page":"17228","DOI":"10.1039\/C9DT04049H","article-title":"Characterisation and influence of lipophilicity on cellular accumulation and cytotoxicity of unconventional Platinum(IV) prodrugs as potent anticancer agents","volume":"48","author":"Deo","year":"2019","journal-title":"Dalton Trans."},{"key":"10.1016\/j.ejmech.2026.118967_bib115","doi-asserted-by":"crossref","first-page":"787","DOI":"10.3390\/pharmaceutics14040787","article-title":"Cyclooxygenase-inhibiting Platinum(IV) prodrugs with potent anticancer activity","volume":"14","author":"Khoury","year":"2022","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.ejmech.2026.118967_bib116","doi-asserted-by":"crossref","first-page":"780","DOI":"10.3390\/pharmaceutics14122780","article-title":"Potent Platinum(IV) prodrugs that incorporate a biotin moiety to selectively target cancer cells","volume":"14","author":"Khoury","year":"2022","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.ejmech.2026.118967_bib117","doi-asserted-by":"crossref","first-page":"16481","DOI":"10.1021\/acs.jmedchem.2c01310","article-title":"Novel Platinum(II) and Platinum(IV) Antitumor agents that exhibit potent cytotoxicity and selectivity","volume":"65","author":"Khoury","year":"2022","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib118","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2025.117734","article-title":"The anti-neoplastic potency of epoxy-substituted polyaromatic Platinum(II) and Platinum(IV) complexes against A549 lung cancer cells","volume":"294","author":"Al Sayegh","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib119","doi-asserted-by":"crossref","first-page":"7005","DOI":"10.1039\/C7DT01054K","article-title":"Characterization and in vitro and in vivo anticancer Activity of Pt(IV) derivatives of [Pt(1S,2S-DACH)(5,6-Dimethyl-1,10-Phenanthroline)]","volume":"46","author":"Harper","year":"2017","journal-title":"Dalton Trans."},{"key":"10.1016\/j.ejmech.2026.118967_bib120","doi-asserted-by":"crossref","first-page":"841","DOI":"10.3748\/wjg.v8.i5.841","article-title":"Less cytotoxicity to combination therapy of 5-Fluorouracil and Cisplatin than 5-Fluorouracil alone in human Colon cancer cell lines","volume":"8","author":"Chen","year":"2002","journal-title":"World J. Gastroenterol."},{"key":"10.1016\/j.ejmech.2026.118967_bib121","doi-asserted-by":"crossref","DOI":"10.1016\/j.jinorgbio.2025.113165","article-title":"Potent anticancer 5-Fluorouracil Platinum(IV) prodrugs","volume":"276","author":"Khoury","year":"2026","journal-title":"J. Inorg. Biochem."},{"key":"10.1016\/j.ejmech.2026.118967_bib122","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3390\/antiox6020029","article-title":"HO-1 induction in cancer progression: a matter of cell adaptation","volume":"6","author":"Nitti","year":"2017","journal-title":"Antioxidants"},{"key":"10.1016\/j.ejmech.2026.118967_bib123","first-page":"23","article-title":"Heme oxygenase inhibition in cancers: possible tools and targets","volume":"22","author":"Podkalicka","year":"2018","journal-title":"Contemp. Oncol. Poznan Pol."},{"key":"10.1016\/j.ejmech.2026.118967_bib124","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ejmech.2018.02.007","article-title":"Potholing of the hydrophobic heme Oxygenase-1 Western Region for the search of potent and selective imidazole-based inhibitors","volume":"148","author":"Salerno","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib125","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1080\/14756366.2021.1928111","article-title":"Novel mutual prodrug of 5-Fluorouracil and heme Oxygenase-1 inhibitor (5-FU\/HO-1 hybrid): design and preliminary in vitro evaluation","volume":"36","author":"Salerno","year":"2021","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib126","doi-asserted-by":"crossref","DOI":"10.1002\/cmdc.202300047","article-title":"Discovery of SI 1\/20 and SI 1\/22 as mutual prodrugs of 5-Fluorouracil and imidazole-based heme oxygenase 1 inhibitor with improved cytotoxicity in DU145 prostate cancer cells","volume":"18","author":"Salerno","year":"2023","journal-title":"ChemMedChem"},{"key":"10.1016\/j.ejmech.2026.118967_bib127","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1124\/pr.107.07104","article-title":"Pharmacological and clinical aspects of heme oxygenase","volume":"60","author":"Abraham","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"10.1016\/j.ejmech.2026.118967_bib128","doi-asserted-by":"crossref","DOI":"10.1080\/14756366.2024.2337191","article-title":"Evaluation of the anticancer effects exerted by 5-Fluorouracil and heme Oxygenase-1 inhibitor hybrids in HTC116 colorectal cancer cells","volume":"39","author":"Salerno","year":"2024","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib129","first-page":"1164","article-title":"Wide expression of the human Erythrocyte glucose transporter Glut1 in human cancers","volume":"56","author":"Younes","year":"1996","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib130","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1089\/dna.2013.2161","article-title":"High glucose modulates antiproliferative effect and cytotoxicity of 5-Fluorouracil in human Colon cancer cells","volume":"33","author":"Ma","year":"2014","journal-title":"DNA Cell Biol."},{"key":"10.1016\/j.ejmech.2026.118967_bib131","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4067\/S0716-97602002000100004","article-title":"Glucose transporters: expression, regulation and cancer","volume":"35","author":"Medina","year":"2002","journal-title":"Biol. Res."},{"issue":"Suppl 1","key":"10.1016\/j.ejmech.2026.118967_bib132","doi-asserted-by":"crossref","first-page":"S197","DOI":"10.1007\/s12032-010-9696-8","article-title":"Overexpression of SGLT1 and EGFR in colorectal cancer showing a correlation with the prognosis","volume":"28","author":"Guo","year":"2011","journal-title":"Med. Oncol. Northwood Lond. Engl."},{"key":"10.1016\/j.ejmech.2026.118967_bib133","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2019.104511","article-title":"Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy","volume":"150","author":"Abdel-Wahab","year":"2019","journal-title":"Pharmacol. Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib134","doi-asserted-by":"crossref","first-page":"E4111","DOI":"10.1073\/pnas.1511698112","article-title":"Functional expression of sodium-glucose transporters in cancer","volume":"112","author":"Scafoglio","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"10.1016\/j.ejmech.2026.118967_bib135","doi-asserted-by":"crossref","first-page":"4450","DOI":"10.1021\/acs.jmedchem.0c00897","article-title":"Targeting colorectal cancer with conjugates of a glucose transporter inhibitor and 5-Fluorouracil","volume":"64","author":"Chang","year":"2021","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib136","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1007\/s00044-025-03401-9","article-title":"Discovery of novel Pterostilbene\/Biphenyl tethered 5-FU based conjugates targeting colorectal cancer: synthesis, cytotoxic and ADMET modeling studies","volume":"34","author":"Becerra-Quintana","year":"2025","journal-title":"Med. Chem. Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib137","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2024.107874","article-title":"Discovery of Daclatasvir as a potential PD-L1 inhibitor from drug repurposing","volume":"153","author":"Sun","year":"2024","journal-title":"Bioorg. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib138","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.2147\/OTT.S130910","article-title":"Mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas","volume":"10","author":"Jain","year":"2017","journal-title":"OncoTargets Ther."},{"key":"10.1016\/j.ejmech.2026.118967_bib139","article-title":"EZH2 inhibitors suppress colorectal cancer by regulating macrophage polarization in the tumor microenvironment","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"10.1016\/j.ejmech.2026.118967_bib140","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/cmdc.201700045","article-title":"Anticancer activity of stilbene-based derivatives","volume":"12","author":"De Filippis","year":"2017","journal-title":"ChemMedChem"},{"key":"10.1016\/j.ejmech.2026.118967_bib141","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.3390\/ijms18122589","article-title":"The role of resveratrol in cancer therapy","volume":"18","author":"Ko","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.ejmech.2026.118967_bib142","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.canlet.2021.05.001","article-title":"Resveratrol for cancer therapy: challenges and future perspectives","volume":"515","author":"Ren","year":"2021","journal-title":"Cancer Lett."},{"key":"10.1016\/j.ejmech.2026.118967_bib143","doi-asserted-by":"crossref","first-page":"12788","DOI":"10.1021\/acs.jafc.9b07860","article-title":"Occurrence, bioavailability, Anti-Inflammatory, and anticancer effects of pterostilbene","volume":"68","author":"Lin","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib144","doi-asserted-by":"crossref","first-page":"e53","DOI":"10.1016\/j.jss.2011.09.054","article-title":"Pterostilbene and cancer: current review","volume":"173","author":"McCormack","year":"2012","journal-title":"J. Surg. Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib145","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ar7000843","article-title":"Hybrid molecules with a dual mode of action: dream or reality?","volume":"41","author":"Meunier","year":"2008","journal-title":"Acc. Chem. Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib146","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12935-022-02561-7","article-title":"A systematic review of the therapeutic effects of resveratrol in combination with 5-Fluorouracil during colorectal cancer treatment: with a special focus on the oxidant, apoptotic, and anti-inflammatory activities","volume":"22","author":"Moutabian","year":"2022","journal-title":"Cancer Cell Int."},{"key":"10.1016\/j.ejmech.2026.118967_bib147","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.canlet.2008.03.052","article-title":"Multi-Targeted therapy of cancer by genistein","volume":"269","author":"Banerjee","year":"2008","journal-title":"Cancer Lett."},{"key":"10.1016\/j.ejmech.2026.118967_bib148","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.3389\/fphar.2019.01336","article-title":"Molecular mechanisms of action of genistein in cancer: recent advances","volume":"10","author":"Tuli","year":"2019","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.118967_bib149","first-page":"177","article-title":"Prospects of and limitations to the clinical applications of genistein","volume":"27","author":"Tang","year":"2019","journal-title":"Discov. Med."},{"key":"10.1016\/j.ejmech.2026.118967_bib150","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.3390\/ph15101299","article-title":"Synthesis and chemopreventive potential of 5-FU\/Genistein hybrids on colorectal cancer cells","volume":"15","author":"Moreno-Quintero","year":"2022","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.ejmech.2026.118967_bib151","doi-asserted-by":"crossref","first-page":"854","DOI":"10.3390\/biology10090854","article-title":"Recent updates on mechanisms of resistance to 5-Fluorouracil and reversal strategies in Colon cancer treatment","volume":"10","author":"Azwar","year":"2021","journal-title":"Biology"},{"key":"10.1016\/j.ejmech.2026.118967_bib152","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1016\/j.drudis.2017.05.014","article-title":"The 1,2,3-Triazole ring as a bioisostere in medicinal chemistry","volume":"22","author":"Bonandi","year":"2017","journal-title":"Drug Discov. Today"},{"key":"10.1016\/j.ejmech.2026.118967_bib153","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.1016\/j.bmc.2019.07.005","article-title":"1,2,3-Triazole-Containing hybrids as leads in medicinal chemistry: a recent overview","volume":"27","author":"Bozorov","year":"2019","journal-title":"Bioorg. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib154","first-page":"245","article-title":"Potential anticancer properties and mechanisms of action of curcumin","author":"Vallianou","year":"2015","journal-title":"Anticancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib155","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1016\/j.nut.2014.02.016","article-title":"Colon carcinogenesis: influence of Western diet-induced obesity and targeting stem cells using dietary bioactive compounds","volume":"30","author":"Kasdagly","year":"2014","journal-title":"Nutrition"},{"key":"10.1016\/j.ejmech.2026.118967_bib156","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/0006-291X(92)90221-6","article-title":"The level of a transcription factor Sp1 is correlated with the expression of EGF receptor in Human Gastric Carcinomas","volume":"189","author":"Kitadai","year":"1992","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.ejmech.2026.118967_bib157","doi-asserted-by":"crossref","first-page":"4550","DOI":"10.1038\/sj.onc.1210234","article-title":"Tumor suppressor Pdcd4 inhibits invasion\/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-Transcription factors","volume":"26","author":"Leupold","year":"2007","journal-title":"Oncogene"},{"key":"10.1016\/j.ejmech.2026.118967_bib158","first-page":"1546","article-title":"Coordinate Up-Regulation of Sp1 DNA-Binding activity and urokinase receptor expression in breast Carcinoma1","volume":"60","author":"Zannetti","year":"2000","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejmech.2026.118967_bib159","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1021\/mp700113r","article-title":"Bioavailability of curcumin: problems and promises","volume":"4","author":"Anand","year":"2007","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.ejmech.2026.118967_bib160","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejmech.2017.07.033","article-title":"Recent advances (2015\u20132016) in Anticancer Hybrids","volume":"142","author":"Kerru","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib161","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.3390\/pharmaceutics15041221","article-title":"New hybrid scaffolds based on 5-FU\/Curcumin: synthesis, cytotoxic, antiproliferative and pro-apoptotic effect","volume":"15","author":"Moreno-Quintero","year":"2023","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.ejmech.2026.118967_bib162","doi-asserted-by":"crossref","DOI":"10.1155\/2013\/963248","article-title":"Review on natural coumarin lead compounds for their pharmacological activity","volume":"2013","author":"Venugopala","year":"2013","journal-title":"BioMed Res. Int."},{"key":"10.1016\/j.ejmech.2026.118967_bib163","doi-asserted-by":"crossref","first-page":"3806","DOI":"10.1016\/j.bmc.2014.05.032","article-title":"Coumarin hybrids as novel therapeutic agents","volume":"22","author":"Sandhu","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib164","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.phytol.2024.01.010","article-title":"Coumarin hybrids for targeted therapies: a promising approach for potential drug candidates","volume":"60","author":"Zeki","year":"2024","journal-title":"Phytochem. Lett."},{"key":"10.1016\/j.ejmech.2026.118967_bib165","doi-asserted-by":"crossref","DOI":"10.3390\/antibiotics14121226","article-title":"Recent developments on coumarin hybrids as antimicrobial agents","volume":"14","author":"Peter","year":"2025","journal-title":"Antibiotics"},{"key":"10.1016\/j.ejmech.2026.118967_bib166","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1002\/asia.201100432","article-title":"Click chemistry: 1,2,3-Triazoles as pharmacophores","volume":"6","author":"Agalave","year":"2011","journal-title":"Chem. Asian J."},{"key":"10.1016\/j.ejmech.2026.118967_bib167","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1002\/cmdc.201402233","article-title":"Are 1,4- and 1,5-Disubstituted 1,2,3-Triazoles good pharmacophoric groups?","volume":"9","author":"Massarotti","year":"2014","journal-title":"ChemMedChem"},{"key":"10.1016\/j.ejmech.2026.118967_bib168","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.3390\/pharmaceutics14102152","article-title":"In vitro antioxidant and pancreatic anticancer activity of novel 5-Fluorouracil-Coumarin conjugates","volume":"14","author":"L\u00f3pez","year":"2022","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.ejmech.2026.118967_bib169","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41514-017-0013-z","article-title":"How does hormesis impact biology, toxicology, and medicine?","volume":"3","author":"Mattson","year":"2017","journal-title":"npj Aging Mech. Dis."},{"key":"10.1016\/j.ejmech.2026.118967_bib170","article-title":"Recent advances on anticancer activity of coumarin derivatives","volume":"5","author":"Rawat","year":"2022","journal-title":"Eur. J. Med. Chem. Rep"},{"key":"10.1016\/j.ejmech.2026.118967_bib171","first-page":"3","article-title":"Introduction to small molecule drug discovery and preclinical development","author":"Southey","year":"2023","journal-title":"Front. Drug Discov."},{"key":"10.1016\/j.ejmech.2026.118967_bib172","doi-asserted-by":"crossref","DOI":"10.1016\/j.drudis.2023.103845","article-title":"Molecular medicinal insights into scaffold hopping-based drug discovery success","volume":"29","author":"Acharya","year":"2024","journal-title":"Drug Discov. Today"},{"key":"10.1016\/j.ejmech.2026.118967_bib173","doi-asserted-by":"crossref","first-page":"12305","DOI":"10.1007\/s13277-014-2543-3","article-title":"Overcoming 5-FU resistance in human non-small cell lung cancer cells by the combination of 5-FU and Cisplatin through the inhibition of glucose metabolism","volume":"35","author":"Zhao","year":"2014","journal-title":"Tumor Biol."},{"key":"10.1016\/j.ejmech.2026.118967_bib174","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-025-23237-y","article-title":"In silico and in vitro evaluation of drug-like properties and anticancer potential of novel 5-Fluorouracil derivatives","volume":"15","author":"Harutyunyan","year":"2025","journal-title":"Sci. Rep."},{"key":"10.1016\/j.ejmech.2026.118967_bib175","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1177\/030089169007600205","article-title":"5-Fluorouracil carcinogenesis in BALB\/c mice","volume":"76","author":"Cavaliere","year":"1990","journal-title":"Tumori Journal"},{"key":"10.1016\/j.ejmech.2026.118967_bib176","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.tig.2023.08.004","article-title":"Whole-genome doubling in tissues and tumors","volume":"39","author":"Vittoria","year":"2023","journal-title":"Trends Genet."},{"key":"10.1016\/j.ejmech.2026.118967_bib177","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1590\/S1415-47572000000100020","article-title":"Image analysis of DNA fragmentation and loss in V79 cells under apoptosis","volume":"23","author":"Maria","year":"2000","journal-title":"Genet. Mol. Biol."},{"key":"10.1016\/j.ejmech.2026.118967_bib178","doi-asserted-by":"crossref","first-page":"647","DOI":"10.3389\/fchem.2020.00647","article-title":"Enzyme-Responsive nanoparticles for anti-tumor drug delivery","volume":"8","author":"Li","year":"2020","journal-title":"Front. Chem."},{"key":"10.1016\/j.ejmech.2026.118967_bib179","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1111\/j.1463-1318.2009.01879.x","article-title":"Capecitabine\/Oxaliplatin as first-line treatment for metastatic colorectal cancer: a meta-analysis","volume":"12","author":"Zhao","year":"2010","journal-title":"Colorectal Dis."},{"key":"10.1016\/j.ejmech.2026.118967_bib180","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/annonc\/mdi047","article-title":"A randomized phase II trial of capecitabine and two different schedules of Irinotecan in first-line treatment of metastatic colorectal cancer: efficacy, quality-of-life and toxicity","volume":"16","author":"Borner","year":"2005","journal-title":"Ann. Oncol."},{"key":"10.1016\/j.ejmech.2026.118967_bib181","first-page":"1","article-title":"Regulatory considerations for prodrug development: safety and efficacy assessments","volume":"15","author":"Guieu","year":"2024","journal-title":"J. Drug Metabol. Toxicol."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426004125?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426004125?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T09:24:45Z","timestamp":1783157085000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523426004125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":181,"alternative-id":["S0223523426004125"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.118967","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Beyond conventional 5-Fluorouracil: Recent medicinal chemistry strategies to enhance its anticancer efficacy","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.118967","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier Masson SAS.","name":"copyright","label":"Copyright"}],"article-number":"118967"}}