Dobrova Aliona, Platzer Sonja, Bacher Felix, Milunovic Miljan N M, Dobrov Anatolie, Spengler Gabriella, Enyedy Éva A, Novitchi Ghenadie, Arion Vladimir B
University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090 Vienna, Austria.
Dalton Trans. 2016 Sep 14;45(34):13427-39. doi: 10.1039/c6dt02784a. Epub 2016 Aug 3.
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.
合成了两种水溶性硫代氨基脲 - 脯氨酸（H₂L(1)）和硫代氨基脲 - 高脯氨酸杂化物（H₂L(2)）。通过H₂L(1)与NiCl₂·6H₂O、PdCl₂和CuCl₂·2H₂O在乙醇中反应，制备了一系列平面正方形配合物[Ni(H₂L(1))Cl]Cl·1.3H₂O (1·1.3H₂O)、[Pd(H₂L(1))Cl]Cl·H₂O (2·H₂O)和[Cu(H₂L(1))Cl]Cl·0.7H₂O (3·0.7H₂O)；从H₂L(2)和CuCl₂·2H₂O在甲醇中反应，得到配合物[Cu(H₂L(2))Cl₂]·H₂O (4·H₂O)。这些化合物通过元素分析、光谱方法（红外光谱、紫外 - 可见光谱和核磁共振光谱）、电喷雾电离质谱和单晶X射线晶体学（H₂L(1)、1、2和4）进行了表征。作为固体，1是抗磁性的，而在甲醇溶液中是顺磁性的。室温下3.26 B.M.的有效磁矩表明溶解时配位几何结构从平面正方形变为八面体。在三种人类癌细胞系（A549、CH1和SW480）和非癌性小鼠胚胎成纤维细胞（NIH/3T3）中研究了配体前体H₂L(1)和H₂L(2)以及金属配合物1 - 4的体外抗癌效力，并且还通过流式细胞术分析了细胞死亡机制。已经建立了明确的构效关系。金属离子以不同方式发挥显著作用：铜（II）增加，而镍（II）和钯（II）降低杂化物的细胞毒性。在所有三种肿瘤细胞系中，H₂L(1)和金属配合物1 - 3的抗增殖活性按以下顺序降低：3 > H₂L(1) > 1 > 2。所研究的金属配合物细胞毒性潜在机制中平面正方形几何结构的作用似乎可以忽略不计，而硫代氨基脲末端氨基和脯氨酸部分的结构修饰对于增强杂化物和铜（II）配合物的抗增殖活性具有重要意义。
