Anticancer potential of 2,2′-bipyridine hydroxamic acid derivatives in head and neck cancer therapy

The genesis of head and neck cancer (HNC) is attributed to the combined influence of genetic and epigenetic irregularities. While surgical resection and radiotherapy remain primary treatment modalities, the effectiveness of current chemotherapeutic options is often hindered by toxicity, resistance, and limited selectivity. Hydroxyurea has long been recognized for its anticancer potential; however, its clinical application is limited by a short half-life, dose-dependent toxicity, and resistance mechanisms. To address these limitations, researchers have focused on developing novel hydroxyurea derivatives with improved pharmacokinetics, target specificity, and multimodal mechanisms of action. In the present study, we report the design and synthesis of two novel 2,2′-bipyridine hydroxamic acid derivatives, including a hydroxyurea analogue aimed at enhancing chemotherapeutic efficacy and safety. Compound 1A demonstrated selective cytotoxicity against Cal27 cells (IC₅₀ = 19.36 μM). Mechanistic investigations revealed that 1A inhibits cancer cell migration and induces ROS-mediated apoptosis. Additionally, 1A exhibited moderate HDAC inhibition, supported by molecular docking and dynamics simulations, which confirmed stable binding to HDAC 2 isoform through Zn²⁺ coordination. These findings place compound 1A as a promising lead candidate, integrating epigenetic modulation and direct cytotoxic effects for potential therapeutic application in HNC.