A novel triazole-dithiocarbamate hybrid synergistically enhances cytarabine efficacy and selectivity in anaplastic large cell lymphoma.

The therapeutic efficacy of cytarabine (Ara-C) in anaplastic large cell lymphoma (ALCL) is frequently compromised by dose-limiting myelosuppression and drug resistance. To address this, we developed a series of novel 1,2,3-triazole-dithiocarbamate hybrids designed to target Aurora A kinase and enhance chemosensitivity to Ara-C. Compound 22h emerged as the lead candidate, exhibiting potent Aurora A inhibition (IC₅₀ = 0.296 μM) with threefold preferential inhibition over Aurora B (IC₅₀ = 0.887 μM) and sub-micromolar activity against ALK (IC₅₀ = 0.332 μM). Molecular docking and 100-ns molecular dynamics simulations suggest that 22h engages a putative allosteric pocket in Aurora A, centered on Cys290 (S-score -13.67 kcal/mol), conferring superior stability over ATP-site binding, while simultaneously forming stable interactions within the ALK hinge region. In ALK+ ALCL SR cells, 22h demonstrated significant cytotoxicity (IC₅₀ = 5.10 μM) and high tumor selectivity (SI = 7.0) relative to normal peripheral blood mononuclear cells. Mechanistically, 22h induced potent G₂/M arrest (3.2-fold increase), supporting Aurora A as the primary functional target, alongside cellular ALK depletion as a complementary mechanism. Furthermore, it triggered mitochondrial apoptosis (17.8% total apoptotic fraction) and dismantled chemoresistance pathways by elevating intracellular ROS (3.5-fold) and inhibiting ALDH1 activity (IC₅₀ = 2.8 μg/mL). Crucially, co-treatment with 22h synergistically potentiated Ara-C efficacy (Combination Index = 0.78), reducing the Ara-C IC₅₀ by 12.8-fold (from 27.65 μM to 2.15 μM) and dramatically widening the therapeutic window by 14-fold (SI = 29.6). These findings identify 22h as a novel multi-target scaffold with potent Aurora A/ALK inhibitory activity that restores Ara-C sensitivity in ALCL, supporting its further development as a precision chemosensitizer.