Novel zinc(II) complexes bearing N,N,N-tridentate pyrimidine ligands as antitumor agents: Synthesis, characterization and antitumor evaluation

Abstract

Herein, a series of Zn(II) complexes (1–4) with a six-coordinate octahedral configuration were successfully designed and synthesized using pyrimidine-pyridine derivatives HL¹-HL⁴. The structures of complexes 1–4 were systematically characterized by ¹H NMR, IR, UV–Vis, X-ray single-crystal diffraction and XRD. MTT assays using selected tumor cell lines (MCF-7, BGC-823, A549, and BEL-7402) demonstrated that complexes 1–4 exhibited superior anti-proliferative activity compared to their corresponding ligands HL¹-HL⁴ and the conventional chemotherapeutic agent cisplatin. Notably, complexes 1–4 showed particularly potent anti-proliferative effects against BGC-823 cells, with IC₅₀ values ranging from 3.22 to 5.73 μM. Importantly, complexes 1–4 displayed significantly lower cytotoxicity toward normal human HL-7702 cells than cisplatin. Based on these findings, complexes 1 and 4, which exhibited the most potent activity against BGC - 823 cells, were selected for further investigation of their apoptosis - inducing mechanisms using Annexin V - FITC/PI double staining, AO/EB double staining, ROS fluorescence intensity detection, mitochondrial membrane potential assessment methods and the Western blot (WB).The results indicated that complexes 1 and 4 effectively suppressed tumor cell proliferation by triggering apoptosis, potentially via processes related to the production of reactive oxygen species (ROS) and mitochondrial impairment. Furthermore, the WB results indicate that complexes 1 and 4 induce tumor cell apoptosis by inhibiting Bcl-2 protein expression and promoting the generation of cleaved caspase-3. In summary, complexes 1–4 exhibit significant promise for the creation of antitumor therapies, providing a novel direction for further investigation and application in tumor treatment.