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

  • Bioorg Chem. 2026 Aug 15:178:109972. doi: 10.1016/j.bioorg.2026.109972.
Heba F Ashour  1 ,  Asmaa S A Yassen  2 ,  Khalid B Selim  3 ,  Magda A A El-Sayed  4 ,  Ahmed T Elhendawy  5 ,  Hosam A Elshihawy  6
Affiliations
  • 1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt.
  • 2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt. Electronic address: [email protected].
  • 3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 4. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt.
  • 5. Physics Department, Faculty of Science, Galala University, New Galala 43713, Egypt.
  • 6. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
PMID: 42119208 DOI: 10.1016/j.bioorg.2026.109972
Abstract

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.

Keywords
1,2,3-Triazole; Anaplastic large cell lymphoma (ALCL); Anaplastic lymphoma kinase (ALK); Aurora A kinase; Chemosensitizer; Cytarabine (Ara-C); Dithiocarbamate; Multi-target inhibitor.
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