Abstract

The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and computational methods. ¹H NMR and acid–base studies have shown that aquo-complexes are the reactive species. Kinetic studies show that both complexes bind covalently to DNA through the metal site and non covalently through the ancillary ligand. Thermal stability studies, viscosity, circular dichroism measurements and quantum chemical calculations have shown that the covalent binding causes breaking of the H-bonding between base pairs, bringing about DNA denaturation and compaction. Additionally, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations shed light into the binding features of the Ru(II) and Ir(III) complexes and their respective enantiomers toward double-helical DNA, highlighting the important role played by the NˆN ancillary ligand once the complexes are covalently linked to DNA. Moreover, metal quantification in the nucleus of SW480 colon adenocarcinoma cells were carried out by inductively coupled plasma–mass spectrometry (ICP–MS), both complexes are more internalized than cisplatin after 4 h of exposition. However, in spite of the dramatic changes in the helicity of the DNA secondary structure induced by these complexes and their nuclear localization, antiproliferative studies have revealed that both, Ru(II) and Ir(III) complexes, cannot be considered cytotoxic. This unexpected behavior can be justified by the fast formation of aquo-complexes, which may react with components of the cell culture medium or the cytoplasm compartment in such a way that they may become deactivated before reaching DNA.

Graphic abstract

中文翻译：

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带有噻菌灵的半三明治Ru（II）和Ir（III）对DNA稳定性产生强烈影响的实验和理论表征。

摘要

用实验和计算方法研究了以噻菌灵为辅助配体的Ru（II）和Ir（III）两个半三明治复合物的合成，表征以及它们的DNA结合能力。^1个1 H NMR和酸碱研究表明，水性络合物是反应性物质。动力学研究表明，两种复合物均通过金属位点与DNA共价结合，而通过辅助配体非共价结合。热稳定性研究，粘度，圆二色性测量和量子化学计算表明，共价结合导致碱基对之间的H键断裂，从而导致DNA变性和紧实。此外，分子动力学（MD）模拟和量子力学/分子力学（QM / MM）计算为Ru（II）和Ir（III）配合物及其各自对映异构体与双螺旋DNA的结合特征提供了亮点，一旦配合物与DNA共价连接，NˆN辅助配体将发挥重要作用。此外，通过电感耦合等离子体质谱法（ICP-MS）对SW480结肠腺癌细胞的细胞核中的金属进行定量分析，暴露4 h后，两种复合物的内在化程度均高于顺铂。然而，尽管由这些复合物及其核定位引起的DNA二级结构的螺旋度发生了巨大变化，抗增殖研究表明Ru（II）和Ir（III）复合物均不能被认为具有细胞毒性。这种意外的行为可以通过快速形成水合复合物来证明，水合复合物可以与细胞培养基或细胞质区室的组分反应，以使其在到达DNA之前就失活。暴露4小时后，两种复合物均比顺铂更内在化。然而，尽管由这些复合物及其核定位诱导的DNA二级结构的螺旋度发生了巨大变化，但抗增殖研究表明，Ru（II）和Ir（III）复合物均不能被认为具有细胞毒性。这种意外的行为可以通过快速形成水合复合物来证明，水合复合物可以与细胞培养基或细胞质区室的组分反应，以使其在到达DNA之前就失活。暴露4小时后，两种复合物均比顺铂更内在化。然而，尽管由这些复合物及其核定位诱导的DNA二级结构的螺旋度发生了巨大变化，但抗增殖研究表明，Ru（II）和Ir（III）复合物均不能被认为具有细胞毒性。这种意外的行为可以通过快速形成水合复合物来证明，水合复合物可以与细胞培养基或细胞质区室的组分反应，以使其在到达DNA之前就失活。Ru（II）和Ir（III）配合物不能被认为具有细胞毒性。这种意外的行为可以通过快速形成水合复合物来证明，水合复合物可以与细胞培养基或细胞质区室的组分反应，以使其在到达DNA之前就失活。Ru（II）和Ir（III）配合物不能被认为具有细胞毒性。这种意外的行为可以通过快速形成水合复合物来证明，水合复合物可以与细胞培养基或细胞质区室的成分发生反应，以使其在到达DNA之前就失活。

图形摘要