{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:01:53Z","timestamp":1785142913402,"version":"3.55.0"},"reference-count":91,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":36,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"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":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Thioredoxin reductase (TrxR), a master regulator of intracellular redox homeostasis, is a validated antitumor target.\n                    <jats:italic>\u03b1,\u03b2<\/jats:italic>\n                    \u2010Unsaturated ketones are potent irreversible TrxR inhibitors with robust in vitro anticancer activity, yet their clinical translation is hindered by critical druggability deficits: poor pharmacokinetics (low solubility, metabolic instability, and low bioavailability) and insufficient tumor selectivity (off\u2010target toxicity and weak tumor tropism). This review systematically summarizes structural optimization strategies to address these limitations. To improve pharmacokinetics, core tactics include introducing polar heterocycles\/hydrophilic groups, modifying skeletons, replacing labile moieties, and hybridizing pharmacophores with subcellular targeting motifs. To enhance tumor selectivity, electronic effect modulation, lipophilicity tuning, scaffold rigidification, tumor\u2010targeting moiety conjugation, and electrophilic center regulation reduce off\u2010target effects. Additionally, tumor\u2010specific redox properties are harnessed to boost intratumoral enrichment. The review further highlights current limitations (e.g., overreliance on natural product modifications, lack of universal SAR frameworks, and inadequate ADME regulation) and prospects future directions: structure\u2010based rational design, tumor microenvironment\u2010responsive prodrugs, multi\u2010target synergism, reversible\u2010irreversible switchable inhibitors, and nanodelivery integration. Collectively, these optimizations lay a theoretical foundation for developing safe, effective TrxR inhibitors to advance precision cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70298","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T06:52:08Z","timestamp":1783493528000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Optimization Strategy for\n                    <i>\u03b1,\u03b2<\/i>\n                    \u2010Unsaturated Ketone TrxR Inhibitors: From Enhanced Pharmacokinetics to Improved Tumor Selectivity"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4996-6223","authenticated-orcid":false,"given":"Xinyan","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory for Candidate Drug Design and Screening Based on Chemical Biology, College of Pharmacy Inner Mongolia Medical University Hohhot 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