Palladium(II) complexes of tridentate bis(benzazole) ligands: Structural, substitution kinetics, DNA interactions and cytotoxicity studies

Abstract

Reactions of 2,6-bis(benzimidazol-2-yl)pyridine (L₁), 2,6-bis(benzoxazol-2-yl)pyridine (L₂), and 2,6-bis(benzothiazol-2-yl)pyridine (L₃) with [Pd(NCMe)₂Cl₂] in the presence of NaBF₄ afforded the corresponding Pd(II) complexes, [Pd(L₁)Cl]BF₄, PdL₁; [Pd(L₂)Cl]BF₄, PdL₂; [Pd(L₃)Cl]BF₄, PdL₃; respectively, while reaction of bis[(1H-benzimidazol-2-yl)methyl]amine (L₄) with [Pd(NCMe)₂Cl₂] afforded complex [Pd(L₄)Cl]Cl, PdL₄. Characterisation of the complexes was accomplished using NMR, IR, MS, elemental analyses and single crystal X-ray crystallography. Ligand substitution kinetics of these complexes by biological nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5'-diphosphate disodium salt (5-GMP) were examined under pseudo-first order conditions. The reactivity of the complexes decreased in the order: PdL₁ > PdL₂ > PdL₃ > PdL₄, ascribed to electronic effects. Density functional theory (DFT) supported this trend. Studies of interaction of the Pd(II) complexes with calf thymus DNA (CT-DNA) revealed strong binding affinities via intercalative binding mode. Molecular docking studies established associative non-covalent interactions between the Pd complexes and DNA. The in vitro cytotoxic activities of PdL₁-PdL₄ were assessed in cancer cell lines HeLa and MRC5-SV2 and a normal cell line MRC-5, using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. PdL₁ exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin's. Complex PdL₁, unlike cisplatin, did not significantly induce caspase-dependent apoptosis.

Keywords: Cytotoxicity; DNA interactions; Pd(II) complexes; Structures; Substitution kinetics.