Two enantiomerically pure thiosemicarbazone-proline conjugates with enhanced aqueous solubility, namely, 2-hydroxy-3-methyl-(S)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [L-Pro-STSC or (S)-H(2)L] and 2-hydroxy-3-methyl-(R)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [D-Pro-STSC or (R)-H(2)L] have been synthesized and characterized by elemental analysis, spectroscopic methods (UV-vis and (1)H and (13)C NMR), and electrospray ionization mass spectrometry. The metal complexation behavior of L-Pro-STSC, stoichiometry, and thermodynamic stability of iron(II), iron(III), copper(II), and zinc(II) complexes in 30% (w/w) dimethyl sulfoxide/H(2)O solvent mixture have been studied by pH-potentiometric, UV-vis-spectrophotometric, circular dichroism, electron paramagnetic resonance, (1)H NMR spectroscopic, and spectrofluorimetric measurements. By the reaction of CuCl(2)·2H(2)O with (S)-H(2)L and (R)-H(2)L, respectively, the complexes [Cu[(S)-H(2)L]Cl]Cl and [Cu[(R)-H(2)L]Cl]Cl have been prepared and comprehensively characterized. An X-ray diffraction study of [Cu[(R)-H(2)L]Cl]Cl showed the formation of a square-planar copper(II) complex, which builds up stacks with interplanar separation of 3.3 Å. The antiproliferative activity of two chiral ligands and their corresponding copper(II) complexes has been tested in two human cancer cell lines, namely, SW480 (colon carcinoma) and CH1 (ovarian carcinoma). The thiosemicarbazone-proline conjugates L- and D-Pro-STSC show only moderate cytotoxic potency with IC(50) values of 62 and 75 μM, respectively, in CH1 cells and >100 μM in SW480 cells. However, the corresponding copper(II) complexes are 13 and 5 times more potent in CH1 cells, based on a comparison of IC(50) values, and in SW480 cells the increase in the antiproliferative activity is even higher. In both tested cell lines, L-Pro-STSC as well as its copper(II) complex show slightly stronger antiproliferative activity than the compounds with a D-Pro moiety, yielding IC(50) values of 4.6 and 5.5 μM for [Cu(L-Pro-STSC)Cl]Cl in CH1 and SW480 cells, respectively.

Two water-soluble thiosemicarbazone-proline (H2L(1)) and thiosemicarbazone-homoproline hybrids (H2L(2)) were synthesised. By reaction of H2L(1) with NiCl2·6H2O, PdCl2 and CuCl2·2H2O in ethanol, the series of square-planar complexes [Ni(H2L(1))Cl]Cl·1.3H2O (1·1.3H2O), [Pd(H2L(1))Cl]Cl·H2O (2·H2O) and [Cu(H2L(1))Cl]Cl·0.7H2O (3·0.7H2O) was prepared, and starting from H2L(2) and CuCl2·2H2O in methanol, the complex [Cu(H2L(2))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 (H2L(1), 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 H2L(1) and H2L(2) 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 H2L(1) and metal complexes 1-3 decreases in all three tumour cell lines in the following rank order: 3 > H2L(1) > 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.

Investigation of the cytotoxic potential of imidazole-derived thiosemicarbazones and their copper(ii) complexes with CHCl2CO2− as a co-ligand.