DNA binding, molecular docking and apoptotic inducing activity of nickel(ii), copper(ii) and zinc(ii) complexes of pyridine-based tetrazolo[1,5-a]pyrimidine ligands

Abstract

Six mononuclear copper(II), nickel(II) and zinc(II) complexes, [ML¹Cl₂] (1–3) and [M(L²)₂Cl₂] (4–6), of two biologically active tetrazolo[1,5-a]pyrimidine core ligands, ethyl 5-methyl-7-pyridine-2-yl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (L¹) and ethyl-5-methyl-7-pyridine-4-yl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (L²), have been synthesized and characterized. The molecular structure of the ligands (L^1&2) and complex 6 were determined by single crystal X-ray diffraction. The X-ray crystal structure of 6 confirms that it has a distorted tetrahedral structure with a ZnN₂Cl₂ coordination environment. All of the complexes exhibit an unusually strong luminescence at room temperature. Electroparamagnetic resonance spectra of copper(II) complexes (2 and 5) show four lines, characteristic of square planar geometry, with nuclear hyperfine spin 3/2. DNA binding studies of complexes with calf-thymus DNA suggest that complexes 2 and 5 bind in the grooves of the DNA. These results were further supported by molecular docking studies. In vitro cytotoxic activities of the ligands (L^1&2) and complexes (1–6) against human cancer cell lines such as lung (A549), cervical (HeLa), colon (HCT-15) and a non-cancer human embryonic kidney cell line revealed that the complexes selectively inhibit the growth of cancer cells and are inactive against non-cancer cell lines, whereas the ligands were found to be inactive with both cancer and non-cancer cell lines. The IC₅₀ values of the complexes revealed that the copper(II) complexes (2 and 5) exhibit high cytotoxic activity against colon (HCT-15) cells when compared to the standard drug cisplatin. Furthermore, the live cell and fluorescent imaging of cancer cells show that complexes 2 and 5 induce cell death through apoptosis.