Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.
Inorg Chem. 2012 Sep 3;51(17):9309-21. doi: 10.1021/ic300967j. Epub 2012 Aug 13.
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.
两种对映体纯的硫代半卡巴腙-脯氨酸缀合物具有增强的水溶性，即 2-羟基-3-甲基-（S）-吡咯烷-2-羧酸-5-甲基苯甲醛硫代半卡巴腙[L-Pro-STSC 或（S）-H（2）L]和 2-羟基-3-甲基-（R）-吡咯烷-2-羧酸-5-甲基苯甲醛硫代半卡巴腙[D-Pro-STSC 或（R）-H（2）L]已通过元素分析、光谱方法（UV-vis 和 1H 和 13C NMR）和电喷雾质谱进行了合成和表征。通过 pH 电位滴定、UV-vis 分光光度法、圆二色性、电子顺磁共振、1H NMR 光谱和荧光光谱测量研究了 L-Pro-STSC 的金属络合行为、化学计量、铁（II）、铁（III）、铜（II）和锌（II）配合物在 30%（w/w）二甲亚砜/H2O 溶剂混合物中的热力学稳定性。通过分别用 CuCl2·2H2O 与（S）-H2L 和（R）-H2L 反应，制备并综合表征了[Cu（（S）-H2L）]Cl]Cl 和[Cu（（R）-H2L）]Cl]Cl 配合物。[Cu（（R）-H2L）]Cl]Cl 的 X 射线衍射研究表明，形成了一个正方形平面铜（II）配合物，其堆积具有 3.3 Å 的平面间分离。两种手性配体及其相应的铜（II）配合物的抗增殖活性在两种人类癌细胞系中进行了测试，即 SW480（结肠癌）和 CH1（卵巢癌）。硫代半卡巴腙-脯氨酸缀合物 L-和 D-Pro-STSC 在 CH1 细胞中的细胞毒性仅具有中等效力，IC50 值分别为 62 和 75 μM，在 SW480 细胞中的 IC50 值大于 100 μM。然而，相应的铜（II）配合物在 CH1 细胞中的效力高 13 倍，基于 IC50 值的比较，而在 SW480 细胞中，增殖活性的增加甚至更高。在两种测试的细胞系中，L-Pro-STSC 及其铜（II）配合物在 CH1 和 SW480 细胞中的抗增殖活性均略强于含有 D-Pro 部分的化合物，其[Cu（L-Pro-STSC）Cl]Cl 的 IC50 值分别为 4.6 和 5.5 μM。
