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New monofunctional platinum(II) and palladium(II) complexes: Studies of the nucleophilic substitution reactions, DNA/BSA interaction, and cytotoxic activity
Journal of Inorganic Biochemistry ( IF 3.8 ) Pub Date : 2018-09-17 , DOI: 10.1016/j.jinorgbio.2018.09.005
Dušan Ćoćić , Snežana Jovanović , Snežana Radisavljević , Jana Korzekwa , Andreas Scheurer , Ralph Puchta , Dejan Baskić , Danijela Todorović , Suzana Popović , Sanja Matić , Biljana Petrović

Four new complexes [Pd(H2LtBu)Cl]Cl (Pd1), [Pt(H2LtBu)Cl]Cl (Pt1), [Pd(Me2LtBu)Cl]Cl (Pd2) and [Pt(Me2LtBu)Cl]Cl (Pt2) (where H2LtBu = 2,6-bis(5-(tert-butyl)-1H-pyrazol-3-yl)pyridine and Me2LtBu = 2,6-bis(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)pyridine) were synthesized and characterized by elemental microanalysis, IR, 1H NMR and ESI-MS methods. The reactivity of complexes towards thiourea (Tu), l-methionine (l-Met), l-cysteine (l-Cys) and guanosine-5′-monophosphate (5′-GMP) was investigated. The obtained order was established as follows: Tu > l-Cys > l-Met > 5′-GMP. Complexes Pd1 and Pt1, that contain H2LtBu as chelator, showed higher reactivity towards biomolecules than those with Me2LtBu. The interaction of complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) was studied by UV–Vis and fluorescence spectroscopy. The results have shown that complexes can bind to DNA exhibiting high binding constants (Kb = 104 M−1). Obtained results during the examination of competitive reaction with ethidium bromide (EB) showed that complexes can replace EB-bound DNA. High values of binding constants indicate good binding affinity of complexes towards BSA. We evaluated the stability differences between complexes based on terpy as well as H2LtBu/Me2LtBu by DFT calculations (B3LYP(CPCM)/LANL2DZp), showing that both tridentate ligand systems lead to complexes of similar stability. The results of biological testing showed that all complexes exert moderate to high selective cytotoxicity, inducing apoptosis and autophagy in HeLa and PANC-1 tumor cell lines. Pd1 exhibited the strongest cytotoxic effect. Finally, cell cycle analysis showed that in HeLa cells Pd1, Pd2 and Pt1 induced accumulation of cells in S phase, whereas in PANC-1 cells Pd2 and Pt1 induced G2/M cycle arrest and Pd1 induced G0/G1 arrest.



中文翻译:

新的单官能铂(II)和钯(II)配合物:亲核取代反应,DNA / BSA相互作用和细胞毒性活性的研究

四个新的复合物[Pd(H 2 L t Bu)Cl] Cl(Pd1),[Pt(H 2 L t Bu)Cl] Cl(Pt1),[Pd(Me 2 L t Bu)Cl] Cl] Cl(Pd2)和[Pt(Me 2 L t Bu)Cl] Cl(Pt2)(其中H 2 L t Bu  = 2,6-双(5-(丁基)-1 H-吡唑-3-基)吡啶和Me 2 L t Bu  = 2,6-双(5-(丁基)-1-甲基-1 H合成并通过元素微分析,IR,1 H NMR和ESI-MS方法对其进行了表征。研究了配合物对硫脲(Tu),1-甲硫氨酸(1- Met),1-半胱氨酸(1 -Cys)和鸟苷-5'-单磷酸酯(5'-GMP)的反应性。所获得的顺序如下建立:Tu>  1- Cys>  1 -Met> 5′-GMP。含有H 2 L t Bu作为螯合剂的配合物Pd1Pt1对生物分子的反应性比具有Me 2 L t Bu的配合物高。通过紫外-可见光谱和荧光光谱研究了配合物与小牛胸腺DNA(CT-DNA)和牛血清白蛋白(BSA)的相互作用。结果表明,复合物可以结合表现出高结合常数(K b  = 10 4  M -1)的DNA 。在检查与溴化乙锭(EB)的竞争反应过程中获得的结果表明,复合物可以取代EB结合的DNA。较高的结合常数值表明复合物对BSA的良好结合亲和力。我们评估了基于terpy以及H 2 L t Bu / Me 2 L t Bu的配合物之间的稳定性差异通过DFT计算(B3LYP(CPCM)/ LANL2DZp),表明两个三齿配体系统均导致相似稳定性的复合物。生物学测试结果表明,所有复合物均具有中等至高选择性的细胞毒性,可诱导HeLa和PANC-1肿瘤细胞系凋亡和自噬。Pd1表现出最强的细胞毒性作用。最后,细胞周期分析表明,在HeLa细胞中Pd1Pd2Pt1诱导了S期细胞的蓄积,而在PANC-1细胞中,Pd2Pt1诱导了G2 / M周期停滞,而Pd1诱导了G0 / G1停滞。

更新日期:2018-09-17
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