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

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. Structural, substitution kinetics, DNA interactions and cytotoxicity of tridentate bis(benzazole) palladium(II) complexes have been studied. Some complexes exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin. [Display omitted] •Pd(II) complexes of 2,6-bis(benzazole) synthesised and characterised•Substitution kinetics of the Pd(II) complexes controlled by electronic effects•Pd(II) complexes exhibit strong interactions with the calf-thymus DNA.•Pd[2,6-bis(benzimidazol-2-yl)pyridine]Cl: comparable cytotoxicity/selectivity to cisplatin•Good correlation between substitution kinetics and cytotoxicity