Design, synthesis and biological assessment of erlotinib-1,2,3-triazole derivatives for anticancer applications.

Current therapeutic strategies for hepatocellular carcinoma (HCC) primarily rely on multi-targeted small molecule agents and immune checkpoint inhibitors. However, clinical trials have demonstrated limited efficacy of erlotinib monotherapy and its combination regimens with monoclonal antibody, highlighting the need for novel therapeutic approaches. In this study, a series of 14 novel erlotinib derivatives incorporating 1,2,3-triazole moieties were designed and synthesized via copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. The MTT assay revealed that compounds 3c and 3d exhibited significant antitumor efficacy against both HepG2 and Huh7 cell lines. Further, investigations revealed that these compounds effectively inhibited cellular proliferation, colony formation, and migration in HepG2 cells in a concentration-dependent manner. The antitumor activity was mediated through the induction of apoptosis, characterized by downregulation of Bcl-2 protein expression and upregulation of cleaved-caspase 3 and cleaved-PARP levels. Notably, compound 3d exhibited in vivo antitumor activity while demonstrating minimal toxicity to normal tissues. These findings collectively suggest that 3d represents a promising candidate for further development as a potential therapeutic agent for hepatocellular carcinoma treatment.