Structure–antiproliferative activity studies on l-proline- and homoproline-4-N-pyrrolidine-3-thiosemicarbazone hybrids and their nickel(ii), palladium(ii) and copper(ii) complexes
Two water-soluble thiosemicarbazone-proline (H2L1) and thiosemicarbazone-homoproline hybrids (H2L2) were synthesised. By reaction of H2L1 with NiCl2·6H2O, PdCl2 and CuCl2·2H2O in ethanol, the series of square-planar complexes [Ni(H2L1)Cl]Cl·1.3H2O (1·1.3H2O), [Pd(H2L1)Cl]Cl·H2O (2·H2O) and [Cu(H2L1)Cl]Cl·0.7H2O (3·0.7H2O) was prepared, and starting from H2L2 and CuCl2·2H2O in methanol, the complex [Cu(H2L2)Cl2]·H2O (4·H2O) was obtained. The compounds have been characterised by elemental analysis, spectroscopic methods (IR, UV-vis and NMR spectroscopy), ESI mass spectrometry and single crystal X-ray crystallography (H2L1, 1, 2 and 4). As a solid, 1 is diamagnetic, while it is paramagnetic in methanolic solution. The effective magnetic moment of 3.26 B.M. at room temperature indicates the change in coordination geometry from square-planar to octahedral upon dissolution. The in vitro anticancer potency of ligand precursors H2L1 and H2L2 and metal complexes 1–4 was studied in three human cancer cell lines (A549, CH1 and SW480) and in noncancerous murine embryonal fibroblasts (NIH/3T3), and the mechanism of cell death was also assayed by flow cytometry. Clear-cut structure–activity relationships have been established. The metal ions exert marked effects in a divergent manner: copper(II) increases, whereas nickel(II) and palladium(II) decrease the cytotoxicity of the hybrids. The antiproliferative activity of H2L1 and metal complexes 1–3 decreases in all three tumour cell lines in the following rank order: 3 > H2L1 > 1 > 2. The role of square-planar geometry in the underlying mechanism of cytotoxicity of the metal complexes studied seems to be negligible, while structural modifications at the terminal amino group of thiosemicarbazide and proline moieties are significant for enhancing the antiproliferative activity of both hybrids and copper(II) complexes.
Royal Society of Chemistry (RSC)
P28223-N34 – Fonds zur Förderung der wissenschaftlichen Forschung (FWF)