Design, Synthesis, and Anticancer Evaluation of Febuxostat-Based Triazolyl Derivatives

Febuxostat, a selective xanthine oxidase inhibitor, was modified via 1,2,3-triazole-based molecular hybridization to generate a series of derivatives with potential anticancer activity. Among them, compounds 8c and 8e exhibited significant antitumor effects across multiple cancer cell lines, particularly in HepG2 cells, with IC 50 values of 6.96 ± 1.76 and 8.56 ± 1.93 μM, respectively. Colony formation assays confirmed that both compounds markedly inhibited tumor cell proliferation. Annexin V-FITC/PI and TUNEL assays further demonstrated that 8c and 8e induced DNA damage and apoptosis in HepG2 cells, as shown by increased γ-H2AX expression and enhanced DNA strand breaks. They also activated intrinsic apoptotic pathways, including the cleavage and activation of caspase-9, caspase-3, and PARP. In vivo, nude mouse xenograft experiments validated their antitumor efficacy, with elevated cleaved caspase-3 levels in tumor tissues. Collectively, these findings indicate that 8c and 8e possess strong therapeutic potential against liver cancer and exhibit promising efficacy and safety profiles.