{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:02:29Z","timestamp":1789970549107,"version":"4.0.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) is a highly lethal malignancy with limited therapeutic options for advanced disease, motivating the development of metal-based agents that can bypass resistance and improve tumor selectivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      This study aimed to evaluate rhenium(I) tricarbonyl complexes bearing 1,10-phenanthroline derivatives, with emphasis on\n                      <jats:italic>fac<\/jats:italic>\n                      -[Re(CO)\n                      <jats:sub>3<\/jats:sub>\n                      (5-chloro-1,10-phenanthroline)Cl] (Re(3)), as potential anti-HCC candidates and to elucidate mechanistic determinants of activity in HepG2 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      Complexes\n                      <jats:italic>fac<\/jats:italic>\n                      -[Re(CO)\n                      <jats:sub>3<\/jats:sub>\n                      (NH\n                      <jats:sub>2<\/jats:sub>\n                      phen)Cl] (Re(1)),\n                      <jats:italic>fac<\/jats:italic>\n                      -[Re(CO)\n                      <jats:sub>3<\/jats:sub>\n                      (NO\n                      <jats:sub>2<\/jats:sub>\n                      phen)Cl] (Re(2)), and Re(3) were synthesized under argon and characterized by\n                      <jats:sup>1<\/jats:sup>\n                      H NMR; electronic structure was examined by DFT (ZORA-PW91\/TZP) with COSMO (water), including global reactivity descriptors and frontier orbital composition. Antiproliferative effects were quantified in HepG2 and non-tumor Vero cells using a 72\u00a0h resazurin assay (1\u2013150\u00a0\u03bcM), while apoptosis, caspase activity, oxidative stress, and signaling changes were assessed by Annexin V\/7-AAD flow cytometry, Caspase-Glo 3\/7, DCFH-DA ROS measurements, western blotting, and immunofluorescence microscopy; statistics used Kruskal\u2013Wallis\/Dunn or ANOVA with\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.05.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and Discussion<\/jats:title>\n                    <jats:p>\n                      Re(3) showed pronounced, selective cytotoxicity (IC\n                      <jats:sub>50<\/jats:sub>\n                      6 \u00b1 1.1\u00a0\u03bcM\u00a0at 72\u00a0h; selective index 5.7; Vero IC\n                      <jats:sub>50<\/jats:sub>\n                      &amp;gt; 30\u00a0\u03bcM), whereas Re(1) and Re(2) were largely inactive (IC\n                      <jats:sub>50<\/jats:sub>\n                      &amp;gt; 100\u00a0\u03bcM). Re(3) induced predominantly apoptotic death (&amp;gt;60% apoptotic cells at 48\u00a0h; minimal necrosis), increased caspase-3\/7 activity (4\u201316\u00a0h), triggered an early ROS burst (1\u201320\u00a0\u03bcM; significant at 2 and 4\u00a0h, comparable to CuSO\n                      <jats:sub>4<\/jats:sub>\n                      ), upregulated cytochrome c, caspase-9 and caspase-3, downregulated Bcl-XL, and increased phosphorylated p53, with negligible extrinsic signaling via caspase-8. DFT indicated Re(3) has a stabilized LUMO (\u22123.34\u00a0eV) and electrophilicity (\u03c9 = 4.32\u00a0eV) with an \u201coptimal\u201d hardness (\u03b7 = 2.37\u00a0eV) supporting sufficient redox reactivity yet kinetic stability; the LUMO localizes (&amp;gt;90%) on the chloro-phenanthroline, consistent with MLCT-driven redox stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Collectively, Re(3) functions as a tuned redox-active agent, triggering apoptosis through the intrinsic pathway. This process possibly involves mitochondrial modulation with tumor selectivity, supporting its advancement as a lead rhenium-based prototype for HCC and motivating\n                      <jats:italic>in vivo<\/jats:italic>\n                      pharmacology and broader HCC panel validation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1926840","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:36:08Z","timestamp":1789968968000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rhenium(I) tricarbonyl complexes with 1,10-phenanthroline derivatives: potential anticancer agents for hepatocellular carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"C\u00e9sar","family":"Z\u00fa\u00f1iga","sequence":"first","affiliation":[{"name":"Instituto de Ciencias Naturales, Facultad de Medicina Veterinaria y Agronom\u00eda, Universidad 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