{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:52:17Z","timestamp":1785523937698,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,27]],"date-time":"2024-10-27T00:00:00Z","timestamp":1729987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Major Project of Research and Development of Shandong Province","award":["2019GSF108226"],"award-info":[{"award-number":["2019GSF108226"]}]},{"name":"Major Project of Research and Development of Shandong Province","award":["81803360"],"award-info":[{"award-number":["81803360"]}]},{"name":"Major Project of Research and Development of Shandong Province","award":["2022KJ111"],"award-info":[{"award-number":["2022KJ111"]}]},{"name":"Major Project of Research and Development of Shandong Province","award":["LCUGYTD2022-04"],"award-info":[{"award-number":["LCUGYTD2022-04"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019GSF108226"],"award-info":[{"award-number":["2019GSF108226"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81803360"],"award-info":[{"award-number":["81803360"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022KJ111"],"award-info":[{"award-number":["2022KJ111"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["LCUGYTD2022-04"],"award-info":[{"award-number":["LCUGYTD2022-04"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u201cYouth Innovation Team Plan\u201d of Shandong Province Higher Education","award":["2019GSF108226"],"award-info":[{"award-number":["2019GSF108226"]}]},{"name":"\u201cYouth Innovation Team Plan\u201d of Shandong Province Higher Education","award":["81803360"],"award-info":[{"award-number":["81803360"]}]},{"name":"\u201cYouth Innovation Team Plan\u201d of Shandong Province Higher Education","award":["2022KJ111"],"award-info":[{"award-number":["2022KJ111"]}]},{"name":"\u201cYouth Innovation Team Plan\u201d of Shandong Province Higher Education","award":["LCUGYTD2022-04"],"award-info":[{"award-number":["LCUGYTD2022-04"]}]},{"name":"Guangyue Young Scholar Innovation Team of Liaocheng University","award":["2019GSF108226"],"award-info":[{"award-number":["2019GSF108226"]}]},{"name":"Guangyue Young Scholar Innovation Team of Liaocheng University","award":["81803360"],"award-info":[{"award-number":["81803360"]}]},{"name":"Guangyue Young Scholar Innovation Team of Liaocheng University","award":["2022KJ111"],"award-info":[{"award-number":["2022KJ111"]}]},{"name":"Guangyue Young Scholar Innovation Team of Liaocheng University","award":["LCUGYTD2022-04"],"award-info":[{"award-number":["LCUGYTD2022-04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Antimetabolite antitumor drugs interfere with nucleic acid and DNA synthesis, causing cancer cell death. However, they also affect rapidly dividing normal cells and cause serious side effects. Doxifluridine (5\u2032-deoxy-5-fluorouridine [5\u2032-DFUR]), a 5-fluorouracil (5-FU) prodrug converted to 5-FU by thymidine phosphorylase (TP), exerts antitumor effects. Since TP is distributed in tumor and normal tissues, 5\u2032-DFUR features side effects. Here we designed a series of novel 5\u2032-DFUR derivatives based on high nitroreductase (NTR) levels in the hypoxic microenvironment of tumor tissues by introducing nitro-containing moieties into the 5\u2032-DFUR structure. These derivatives exert their antitumor effects by producing 5-FU under the dual action of TP and NTR in the tumor microenvironment. The derivatives were synthesized and their stability, release, and cytotoxicity evaluated in vitro and antitumor activity evaluated in vivo. Compound 2c, featuring nitrofuran fragments, was stable in phosphate-buffered saline and plasma at different pH values and reduced rapidly in the presence of NTR. The in vitro cytotoxicity evaluation indicated that compound 2c showed excellent selectivity in the MCF-7 and HT29 cell lines. Moreover, it exhibited antitumor effects comparable to those of 5\u2032-DFUR in vivo without significant toxic side effects. These results suggest that compound 2c is a promising antitumor prodrug.<\/jats:p>","DOI":"10.3390\/molecules29215077","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T07:47:18Z","timestamp":1730101638000},"page":"5077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design, Synthesis, and Evaluation of Doxifluridine Derivatives as Nitroreductase-Responsive Anticancer Prodrugs"],"prefix":"10.3390","volume":"29","author":[{"given":"Xinmeng","family":"Zhang","sequence":"first","affiliation":[{"name":"National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taimin","family":"Dong","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Li","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changjie","family":"Xu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanghui","family":"Chen","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiben","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1457-0050","authenticated-orcid":false,"given":"Xuekun","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s40425-016-0163-8","article-title":"5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers","volume":"4","author":"Goel","year":"2016","journal-title":"J. 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