American Chemical Society
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l- and d‑Proline Thiosemicarbazone Conjugates: Coordination Behavior in Solution and the Effect of Copper(II) Coordination on Their Antiproliferative Activity

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journal contribution
posted on 2015-12-16, 21:50 authored by Miljan N. M. Milunovic, Éva A. Enyedy, Nóra V. Nagy, Tamás Kiss, Robert Trondl, Michael A. Jakupec, Bernhard K. Keppler, Regina Krachler, Ghenadie Novitchi, Vladimir B. Arion
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)-H2L] and 2-hydroxy-3-methyl-(R)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [d-Pro-STSC or (R)-H2L] have been synthesized and characterized by elemental analysis, spectroscopic methods (UV–vis and 1H and 13C 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/H2O solvent mixture have been studied by pH-potentiometric, UV–vis-spectrophotometric, circular dichroism, electron paramagnetic resonance, 1H NMR spectroscopic, and spectrofluorimetric measurements. By the reaction of CuCl2·2H2O with (S)-H2L and (R)-H2L, respectively, the complexes [Cu­[(S)-H2L]­Cl]Cl and [Cu­[(R)-H2L]­Cl]Cl have been prepared and comprehensively characterized. An X-ray diffraction study of [Cu­[(R)-H2L]­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 IC50 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 IC50 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 IC50 values of 4.6 and 5.5 μM for [Cu­(l-Pro-STSC)­Cl]Cl in CH1 and SW480 cells, respectively.