Zinc complex with quinoline-based thiazolyl-hydrazone targeting DNA replication in cancer cells

The development of selective anticancer agents remains a central objective in medicinal chemistry. Here, we report the synthesis, structural characterization, and biological evaluation of the first metal complex of a quinoline-based thiazolyl-hydrazone ligand [(E)-2-(8-(quinolin-2-ylmethylene)hydrazinyl)-4-(4-tolyl)-1,3-thiazole)] (HL). Obtained octahedral Zn(II) complex [Zn(HL)₂](NO₃)₂, (1), is based on two NNN tridentate coordinated ligands. In vitro cytotoxicity assays revealed that the complex exhibits potent and selective activity against lung adenocarcinoma A-549 and colorectal carcinoma HCT-116, while sparing non-tumorigenic human embryonic kidney HEK-293 cells. Mechanistic studies demonstrated that the complex induces S-phase arrest, inhibits DNA synthesis, and triggers significant DNA damage as indicated by increased p-γH2AX expression. These effects were accompanied by mitochondrial depolarization, caspase-3/7 activation, and phosphatidylserine externalization, confirming apoptosis via the intrinsic pathway. The compound further inhibited tumor growth in 3D spheroids and the chick chorioallantoic membrane model without overt toxicity. Compared to the free ligand and reference chemotherapeutics, the zinc complex showed improved efficacy and selectivity. These results highlight the potential of metal coordination to enhance the biological activity of hybrid ligands, supporting further development of this class of compounds as selective anticancer agents.