Design, synthesis, and mechanistic elucidation of lawsone derivatives as novel inducers of ROS-associated mitochondrial apoptosis in breast cancer

AIM: Novel monomeric and dimeric lawsone derivatives were designed and investigated for their cytotoxicity. METHOD: Lawsone derivatives (2-8) were synthesized under solvent-free conditions and tested against MDA-MB-231 and MCF-7 breast cancer cells versus doxorubicin. Mechanistic studies included reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔΨm), cell-cycle distribution, apoptosis, and apoptosis-related genes. RESULTS: ) phase cell cycle arrest and promoted apoptosis with minimal necrosis. Compound 7 significantly upregulated Bcl-2-associated X protein (Bax) (6.6-fold) and caspase-9 (8.0-fold) while downregulating B-cell lymphoma 2 (Bcl-2) and poly (ADP-ribose) polymerase 1 (PARP-1), supporting activation of the intrinsic mitochondrial apoptotic pathway. CONCLUSION: Dimerization substantially enhanced the anticancer potency and selectivity of the lawsone scaffold. Compounds 7 and 8 represent promising lead structures for further optimization and development of potent anticancer agents.