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<p>A series of febuxostat–1,2,3-triazole derivatives were designed and synthesized to investigate their structure–activity relationships (SARs) and anticancer mechanisms. Their cytotoxic activities were evaluated against human lung cancer cell lines (A549, PC-9, and H460). Several compounds exhibited notable antiproliferative activity against PC-9 and H460 cells while showing low toxicity toward normal L02 hepatocytes. Among them, compound <b>14h</b> displayed the most potent activity, with IC₅₀ values of 13.87 ± 0.25 µM (A549), 3.81 ± 0.50 µM (PC-9), and 10.01 ± 0.03 µM (H460). Further biological studies revealed that 14h significantly inhibited tumor cell proliferation in a dose-dependent manner and primarily induced apoptosis in A549 and H460 cells, accompanied by the activation of autophagy. In addition, <b>14h</b> markedly triggered DNA damage, as evidenced by increased DNA strand breaks and elevated γH2AX expression. RT-PCR and Western blot analyses further demonstrated that 14h regulated the expression of key genes and proteins associated with oxidative stress, DNA damage response, apoptosis, and autophagy, including p21, Bcl-2, caspase-6, Keap1, H2AX, ATG7, γH2AX, LC3, caspase-9, and PARP. Molecular docking analysis suggested that 14h could effectively bind to the active site of PARP through hydrogen bonding and π–π interactions with key residues, potentially contributing to DNA damage accumulation. Collectively, these findings indicate that compound 14h exerts potent anticancer activity through DNA damage–mediated activation of apoptotic and autophagic pathways, highlighting febuxostat–triazole hybrids as promising candidates for lung cancer therapy.</p>

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Structure–activity relationship studies of febuxostat derivatives identify potent anti-lung cancer agents that induce DNA damage and autophagy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月21日

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  • Xixi Hou,
  • Xuanwei Zhang,
  • Jingjing Guo,
  • Yajie Guo,
  • Jianxue Yang

摘要

A series of febuxostat–1,2,3-triazole derivatives were designed and synthesized to investigate their structure–activity relationships (SARs) and anticancer mechanisms. Their cytotoxic activities were evaluated against human lung cancer cell lines (A549, PC-9, and H460). Several compounds exhibited notable antiproliferative activity against PC-9 and H460 cells while showing low toxicity toward normal L02 hepatocytes. Among them, compound 14h displayed the most potent activity, with IC₅₀ values of 13.87 ± 0.25 µM (A549), 3.81 ± 0.50 µM (PC-9), and 10.01 ± 0.03 µM (H460). Further biological studies revealed that 14h significantly inhibited tumor cell proliferation in a dose-dependent manner and primarily induced apoptosis in A549 and H460 cells, accompanied by the activation of autophagy. In addition, 14h markedly triggered DNA damage, as evidenced by increased DNA strand breaks and elevated γH2AX expression. RT-PCR and Western blot analyses further demonstrated that 14h regulated the expression of key genes and proteins associated with oxidative stress, DNA damage response, apoptosis, and autophagy, including p21, Bcl-2, caspase-6, Keap1, H2AX, ATG7, γH2AX, LC3, caspase-9, and PARP. Molecular docking analysis suggested that 14h could effectively bind to the active site of PARP through hydrogen bonding and π–π interactions with key residues, potentially contributing to DNA damage accumulation. Collectively, these findings indicate that compound 14h exerts potent anticancer activity through DNA damage–mediated activation of apoptotic and autophagic pathways, highlighting febuxostat–triazole hybrids as promising candidates for lung cancer therapy.