Palladium(ii) complexes bearing 1-iminothiolate-3,5-dimethylpyrazoles: synthesis, cytotoxicity, DNA binding and enzymatic inhibition studies

Abstract

Four palladium(II) compounds of general formulae [PdCl(L_n)(PPh₃)] {L₁ = 3,5-dimethylpyrazole-1-iminothiolate (1); L₂ = 3,5-dimethyl-pyrazole-N-methyl-1-iminothiolate (2); L₃ = 3,5-dimethylpyrazole-N-ethyl-1-iminothiolate (3); L₄ = 3,5-dimethylpyrazole-N-phenyl-1-iminothiolate (4); and PPh₃ = triphenylphosphine} have been synthesized. The novel synthesized compounds have been characterized by C, H and N elemental analysis, 1D (¹H and ¹³C) and 2D (HSQC and HMBC) NMR, MS, FT-IR, and molar electrical conductivity measurements. The molecular structure of complex 3 has been solved by single-crystal X-ray crystallography. The stability of the complexes in solution was studied in a DMSO/D₂O (7 : 3) solution after 48 h. The antiproliferative activity of all free ligands and the stable palladium complexes 2–4 was assayed using the human breast tumour cell line MCF-7, lung tumour cell line A549 and human fetal lung fibroblast cell line MRC-5. Complex 3 was more active than cisplatin against MCF-7 cells, whilst palladium compounds 2–4 exhibited no drug response towards A549 cells at concentrations <50 μM. The binding properties of compounds 2 and 3 to ct-DNA have been studied using circular dichroism and fluorescence spectroscopy. The topoisomerase IIα inhibition has been studied for complex 2 and 3. The ability of all complexes to inhibit the activity of cathepsin B and L has also been investigated in this work. Compound 4 inhibited more than 50% of the cathepsin B activity at a concentration of 10 μM. Docking simulations have been carried out to gain more information about the interaction of the complexes and cathepsin B.