PDF(Pubmed)
Abstract：
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 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL1), 6-morpholinomethyl-2-acetylpyridine 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL2), and 6-morpholinomethyl-2-formylpyridine 4N-phenyl-3-thiosemicarbazone (HL3), and mono-ligand nickel(II), zinc(II) and palladium(II) complexes with HL1, namely [CoIII(HL1)(L1)](NO3)2 (1), [CoIII(HL2)(L2)](NO3)2 (2), [CoIII(HL3)(L3)](NO3)2 (3), [FeIII(L2)2]NO3 (4), [FeIII(HL3)(L3)](NO3)2 (5), [NiII(L1)]Cl (6), [Zn(L1)Cl] (7) and [PdII(HL1)Cl]Cl (8). We discuss the effect of the metal identity and metal complex stoichiometry on in vitro 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.
摘要：
最近，我们发现具有异构体吗啉-氨基硫脲杂合配体的铜（II）配合物在癌细胞中显示出良好的细胞毒性，并且负责该活性的分子靶标可能是微管蛋白。为了获得更好的候选药物，我们选择利用配位化学的力量（i）组装球形结构以更好地适应秋水仙碱口袋和（ii）改变金属离子。我们报告了双配体钴（III）和铁（III）与6-吗啉基甲基-2-甲酰吡啶4N-（4-羟基-3,5-二甲基苯基）-3-氨基硫脲（HL1）的配合物的合成和完整表征，6-吗啉基甲基-2-乙酰基吡啶4N-（4-羟基-3,5-二甲基苯基）-3-氨基硫脲（HL2），和6-吗啉基甲基-2-甲酰吡啶4N-苯基-3-氨基硫脲（HL3），和单配体镍(II)，锌（II）和钯（II）与HL1的配合物，即[CoIII（HL1）（L1）]（NO3）2（1），[CoIII(HL2)(L2)](NO3)2(2)，[CoIII(HL3)(L3)](NO3)2(3)，[FeIII(L2)2]NO3(4),[FeIII(HL3)(L3)](NO3)2(5)，[NiII(L1)]Cl(6),[Zn(L1)Cl](7)和[PdII(HL1)Cl]Cl(8)。我们商量了金属身分和金属配合物化学计量对体外细胞毒性和抗微管卵白活性的影响。复合物4的高抗增殖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抗增殖活性机制的见解。
