Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 42, A-1090 Vienna, Austria.
Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, SK-81237 Bratislava, Slovakia.
Dalton Trans. 2024 Jul 23;53(29):12349-12369. doi: 10.1039/d4dt01469c.
Quite recently we discovered that copper(II) complexes with isomeric morpholine-thiosemicarbazone hybrid ligands show good cytotoxicity in cancer cells and that the molecular target responsible for this activity might be tubulin. In order to obtain better lead drug candidates, we opted to exploit the power of coordination chemistry to (i) assemble structures with globular shape to better fit the colchicine pocket and (ii) vary the metal ion. We report the synthesis and full characterization of bis-ligand cobalt(III) and iron(III) complexes with 6-morpholinomethyl-2-formylpyridine 4-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL1), 6-morpholinomethyl-2-acetylpyridine 4-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL2), and 6-morpholinomethyl-2-formylpyridine 4-phenyl-3-thiosemicarbazone (HL3), and -ligand nickel(II), zinc(II) and palladium(II) complexes with HL1, namely Co(HL)(L) (1), Co(HL)(L) (2), Co(HL)(L) (3), [Fe(L)]NO (4), Fe(HL)(L) (5), [Ni(L)]Cl (6), [Zn(L)Cl] (7) and [Pd(HL)Cl]Cl (8). We discuss the effect of the metal identity and metal complex stoichiometry on cytotoxicity and antitubulin activity. The high antiproliferative activity of complex 4 correlated well with inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity were supported by experimental results and molecular docking calculations.
最近，我们发现铜（II）配合物与异构吗啉-硫代半卡巴腙混合配体在癌细胞中表现出良好的细胞毒性，而负责这种活性的分子靶标可能是微管蛋白。为了获得更好的先导药物候选物，我们选择利用配位化学的力量（i）组装具有球形结构的结构，以更好地适应秋水仙素口袋，（ii）改变金属离子。我们报告了双配体钴（III）和铁（III）配合物的合成和全表征，这些配合物具有 6-吗啉甲基-2-甲酰基吡啶 4-（4-羟基-3,5-二甲基苯基）-3-硫代半卡巴腙（HL1），6-吗啉甲基-2-乙酰基吡啶 4-（4-羟基-3,5-二甲基苯基）-3-硫代半卡巴腙（HL2）和 6-吗啉甲基-2-甲酰基吡啶 4-苯基-3-硫代半卡巴腙（HL3），以及-配体镍（II）、锌（II）和钯（II）配合物与 HL1，即[Co（HL）（L）]（NO）（1），[Co（HL）（L）]（NO）（2），[Co（HL）（L）]（NO）（3），[Fe（L）]NO（4），[Fe（HL）（L）]（NO）（5），[Ni（L）]Cl（6），[Zn（L）Cl]（7）和[Pd（HL）Cl]Cl（8）。我们讨论了金属身份和金属配合物化学计量对细胞毒性和抗微管蛋白活性的影响。配合物 4 的高增殖抑制活性与微管蛋白聚合的抑制密切相关。实验结果和分子对接计算支持了对增殖抑制活性机制的深入了解。
