Dihydropyrimidinone–isatin hybrids as potent inducers of cell-cycle arrest and caspase-dependent apoptosis in MV4-11 acute myeloid leukemia cells
A novel series of 1H-1,2,3-triazole-linked dihydropyrimidinone (DHPM)–isatin hybrids was designed, synthesized and evaluated for antiproliferative activity against MV4-11 (acute myeloid leukemia), LN229 (glioblastoma) and SHSY-5Y (neuroblastoma). Among the synthesized derivatives, compound 7k, bearing a propyl-linked dibromoisatin-DHPM core, emerged as the most potent analogue, exhibiting an IC50 of 0.8 ± 0.1 µM in MV4-11 cells, significantly surpassing cisplatin (IC50 = 4.5 ± 0.2 µM), while showing low toxicity toward HaCaT cells, indicating good selectivity (SI = 37.12) as compared to cisplatin (SI = 7.62). Mechanistic studies demonstrated that 7k induced G0/G1 phase arrest in MV4-11 cells and elevated intracellular ROS levels, promoting mitochondrial dysfunction. The ROS induction strongly correlated with caspase activation and enhanced apoptotic cell death. Overall, the cytotoxic effects of 7k on MV4-11 cells are attributed to the coordinated induction of ROS-mediated oxidative stress, G0/G1 cell cycle arrest, and caspase-dependent apoptosis, highlighting its promising antiproliferative potential.