Design, synthesis, and evaluation of 1,4-naphthoquinone-chromene hybrids as potential anti-K562 and A549 agents

Abstract

Two series of 1,4-naphthoquinone-chromone hybrids 4a (4aa–4ao) and 4b (4ba–4bq) were designed, synthesized and evaluated as antitumor agents. Most of the compounds exhibited moderate to excellent cytotoxicity to tumor cells (K562 and A549), especially the 4a series compounds that showed equal or stronger antiproliferative activity compared to positive control cisplatin on two different types of cells (except for 4al and 4an). Among them, compound 4ac showed significant inhibitory activity on A549 cells with an IC₅₀ value of 2.93 μM, and was 5.2 times more active than cisplatin (IC₅₀ = 15.32 ± 2.64 μM). Meanwhile, AO/EB staining, flow cytometry, cell morphology, and ultrastructural analysis revealed that compound 4ac could induce A549 cell apoptosis and arrest at the G1 phase. Further mechanism studies speculated that compound 4ac may regulate the p53-MDM2 pathway, alter the Bax/Bcl-2 ratio to release Cyt c, activate the mitochondrial apoptosis pathway to induce cell apoptosis, and inhibit A549 cell proliferation through cycle arrest. Collectively, compound 4ac could be used as a potential candidate compound for anti-lung cancer drugs.