Synthesis and in vitro antiproliferative activity of dolutegravir derivatives against hepatocellular carcinoma via apoptosis-related mechanisms

Abstract

Drug repurposing through structural modification of marketed drugs is a well-established strategy for the discovery of novel therapeutic agents, benefiting from known safety profiles and clinical relevance. Dolutegravir, a widely used HIV integrase inhibitor featuring a nitrogen–oxygen heterocycle, provides an attractive scaffold for exploring new pharmacological activities. In this study, a series of novel dolutegravir derivatives bearing 1,2,3-triazole moieties were synthesized via click chemistry and evaluated for their antitumor activity against hepatocellular carcinoma (HCC). Among them, compounds 3b and 3i exhibited potent antiproliferative activity against HepG2 cells, with IC50 values of 7.89 µM and 15.07 µM, respectively. Both compounds also showed significant inhibitory activity against Huh7 cells, with IC50 values of 2.94 µM for 3b and 4.69 µM for 3i. Further biological studies demonstrated that compounds 3b and 3i significantly induced apoptosis in HepG2 cells, inhibited cell migration in wound-healing assays, and suppressed colony formation. Mechanistic investigations in Huh7 cells further revealed that compound 3b induced concentration-dependent cell death and apoptosis, accompanied by enhanced autophagy and DNA damage. These antitumor effects were associated with significant alterations in apoptosis- and migration-related protein expression. Collectively, these findings demonstrate that dolutegravir-based 1,2,3-triazole derivatives possess promising anti-hepatocellular carcinoma activity and identify compound 3b as a potential lead candidate for further anticancer drug development.