Novel tetranuclear grid-like Zn(ii) complexes derived from dihydrazone pyrimidine derivatives as antitumor agents

Abstract

Due to the antitumor properties, Zn(II) complexes have attracted more and more attention. Herein, three novel tetranuclear Zn(II) complexes 1–3 based on dihydrazone pyrimidine derivatives H₂L¹–H₂L³ were synthesized and characterized using IR spectroscopy, ¹H NMR spectroscopy, single crystal X-ray diffraction analysis, XRD, TG and elemental analysis. Single crystal X-ray diffraction analysis revealed that 1–3 all displayed a [2 × 2] grid-like topology. The stability in solution, lipophilicity, confocal imaging and antitumor activities were investigated. Complexes 1–3 displayed high structural stability, membrane permeability and different lipophilicities. They can target mitochondria due to the cation charge. The MTT assay indicated that all of them exhibited stronger antiproliferative activity than the corresponding derivatives H₂L¹–H₂L³ and the well-known cisplatin against all the selected tumor cells (BGC-823, BEL-7402, MCF-7 and A549), with IC₅₀ values ranging from 2.83 μM to 7.97 μM. AO/EB double staining, flow cytometry and ROS detection suggested that complexes 1 and 2 could induce BGC-823 apoptosis in a dose-dependent manner. UV-Vis spectra, CD spectra, viscosity analysis and molecular docking revealed that complexes 1 and 2 interact with DNA mainly via partial intercalation and groove binding. Tetranuclear [2 × 2] grid-like Zn(II) complexes have the potential to be promising antitumor agents in the future.