{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:51:02Z","timestamp":1791183062221,"version":"4.1.0"},"reference-count":99,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A new class of pyrimidine nucleoside dimers featuring an ultrashort 1,4\u2010disubstituted 1,2,3\u2010triazole linker was designed and synthesized to explore the biological potential of structurally robust nucleoside analogues as anticancer agents. The target compounds were efficiently obtained via Cu(I)\u2010catalyzed azide\u2010alkyne cycloaddition (CuAAC) from appropriately functionalized 3\u2032\u2010azido\u2010 and 4\u2032\u2010ethynyl\u20105\u2032\u2010deoxy\u20105\u2032\u2010nor nucleoside precursors and fully characterized by multinuclear 1D\/2D NMR spectroscopy and ESI\u2010MS. Their antiproliferative activity was evaluated against a panel of human cancer cell lines comprising cervical (HeLa), breast (T47D), ovarian (SK\u2010OV\u20103), and glioblastoma (U\u2010138 MG and U\u2010251 MG) cells, with MRC\u20105 human fibroblasts serving as the control. Several dimers displayed pronounced and cell line\u2010selective antiproliferative activity while exhibiting limited toxicity toward normal cells. Dimers\n                    <jats:bold>4<\/jats:bold>\n                    ,\n                    <jats:bold>9<\/jats:bold>\n                    ,\n                    <jats:bold>11<\/jats:bold>\n                    , and\n                    <jats:bold>17<\/jats:bold>\n                    demonstrated the highest activity against HeLa cells, whereas Dimers\n                    <jats:bold>7<\/jats:bold>\n                    and\n                    <jats:bold>15<\/jats:bold>\n                    were the most potent against U\u2010251 MG glioblastoma cells, with activities comparable to or exceeding that of 5\u2010fluoro\u20102\u2032\u2010deoxyuridine (5FdU). Mechanistic studies performed on the most active glioblastoma\u2010directed dimers revealed a concentration\u2010dependent reduction in clonogenic survival and cell migration, accompanied by increased cell death and pronounced S\u2010phase cell cycle arrest, closely resembling the effect of the reference compound 5FdU. In contrast, only a modest and transient increase in intracellular reactive oxygen species (ROS) was detected, indicating that oxidative stress is unlikely to represent the primary mechanism responsible for their antiproliferative activity. Preliminary structure\u2013activity relationship analysis demonstrated that both the nature of the nucleobase and the rigid triazole\u2010linked dimeric architecture substantially influence biological activity and selectivity. Moreover, the synthesized dimers exhibited excellent chemical stability in cell culture medium and human serum, highlighting their exceptional resistance to degradation. Taken together, these findings identify triazole\u2010linked pyrimidine nucleoside dimers as highly stable bioactive scaffolds that inhibit glioblastoma cell proliferation through disruption of DNA synthesis rather than oxidative stress and represent promising candidates for further development as anticancer agents or durable nucleic acid\u2010targeting molecular tools.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70407","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:52:57Z","timestamp":1791179577000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Triazole\u2010Linked Pyrimidine Nucleoside Dimers: Design, Synthesis, and Applications in Medicinal and Nucleic Acid Chemistry. Part\n                    <scp>IV<\/scp>"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0970-8297","authenticated-orcid":false,"given":"Dagmara","family":"Baraniak","sequence":"first","affiliation":[{"name":"Institute of Bioorganic Chemistry, Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6128-5383","authenticated-orcid":false,"given":"Dariusz","family":"Wawrzyniak","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry, Polish Academy of Sciences  Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4346-4804","authenticated-orcid":false,"given":"Daniel","family":"Baranowski","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry, Polish Academy of Sciences  Pozna\u0144 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