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

Abstract

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 IC₅₀ 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.