Anticancer activity of Ni(ii) and Zn(ii) complexes based on new unsymmetrical salophen-type ligands: synthesis, characterization and single-crystal X-ray diffraction

Abstract

The discovery of new coordination compounds with anticancer properties is an active field of research due to the severe side effects of platinum-based compounds currently used in chemotherapy. In the search for new agents for the treatment of cancer, unsymmetrical N₂O₂-tetradentate ligand (H₂L¹ and H₂L²) and their Ni(II) and Zn(II) asymmetric complexes (Ni^II-L^1–2 and Zn^II-L^1–2) have been synthesized and fully characterized. ¹H NMR studies revealed that the ligands and complexes were stable in mixtures of DMSO : D₂O (9 : 1). Complementary UV-Vis studies confirmed that Zn^II derivatives also exhibit high stability in mixtures DMSO : buffer (6 : 4) after 24 h. Single-crystal X-ray diffraction studies confirmed the molecular structures of H₂L¹, H₂L², Ni^II-L¹, and Ni^II-L². At the molecular level, complexes were completely planar without significant distortions of the square-planar geometry according to τ₄ parameter. Furthermore, the crystalline structures revealed non-classical intermolecular interactions of the C–H⋯O and the Ni⋯Ni type. The ligands and complexes were screened against the human osteosarcoma (MG-63), human colon cancer (HCT-116), breast cancer (MDA-MB-231) cell lines, and non-cancerous cells (L929). H₂L¹ and H₂L² ligands not caused cytotoxic effects at a concentration of 100 μM, while Ni^II-L², Zn^II-L¹, and Zn^II-L² complexes induce cytotoxic effects in all cell lines. Ni^II-L² was a more active complex against MG-63 (3.9 ± 1.5) and HCT-116 (3.4 ± 1.7) cell lines with IC₅₀ values in the low micromolar range. In addition, this compound was 10-, 5-, and 11-fold more potent than cisplatin in MG-63 (39 ± 1.8), HCT-116 (17.2), and MDA-MB-231 (131 ± 18), respectively. Three complexes exhibited great selectivity for tumoral cells with SI values ranging from 1.6 to 7.4.