Mechanistic Insight for Targeting Biomolecules by Ruthenium(II) NSAID Complexes,ACS Applied Bio Materials

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Mechanistic Insight for Targeting Biomolecules by Ruthenium(II) NSAID Complexes
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-06-22 , DOI: 10.1021/acsabm.0c00501
Chanchal Sonkar ₁ , Novina Malviya ₂ , Rishi Ranjan ₂ , Srimanta Pakhira _{3,

4} , Suman Mukhopadhyay _{1,

2}

Affiliation

With the enormous progress in ruthenium complexes as promising anticancer agents after the entry of KP1019, KP1339, and NAMI-A in clinical trials, herein three arene ruthenium(II) NSAID (nonsteroidal anti-inflammatory drugs) complexes viz. [Ru(η⁶-p-cymene)(mef)Cl] (1), [Ru(η⁶-p-cymene)(flu)Cl] (2), and [Ru(η⁶-p-cymene)(dif)Cl] (3) are synthesized, characterized, and reported. Density functional theory (DFT) calculations were performed in support of the obtained experimental results by computing the equilibrium geometries, reactions pathways, relative Gibbs free energy, stability, and reactions barriers of the complexes. The present theoretical study shows that all the proposed structures of the complexes are energetically stable and favorable, and the results obtained are in close accordance with the experiment. Further, the in vitro cytotoxicity of the complexes was explored through MTT assay on MCF-7, Hela, A549, and HEK cell lines. It was found the complex 1 and 2 are significantly cytotoxic toward the MCF-7 cell line. These complexes have also shown a strong affinity toward CT-DNA and proteins (HSA and BSA) as analyzed through spectroscopic techniques. Further investigation of the mechanism of cell death of selected complexes was carried out by various staining, flow cytometry, and gene expression analysis obtained by RT-PCR.

中文翻译：

钌 (II) NSAID 配合物靶向生物分子的机理研究

随着KP1019、KP1339和NAMI-A进入临床试验后，钌配合物作为有前途的抗癌药物取得了巨大进展，本文提出了三种芳烃钌(II) NSAID（非甾体类抗炎药）配合物。[Ru(η ⁶ - p -cymene)(mef)Cl] ( 1 )、[Ru(η ⁶ - p -cymene)(flu)Cl] ( 2 ) 和 [Ru(η ⁶ - p -cymene)( dif)Cl] ( 3)被合成、表征和报道。通过计算配合物的平衡几何、反应路径、相对吉布斯自由能、稳定性和反应势垒，进行密度泛函理论 (DFT) 计算以支持获得的实验结果。目前的理论研究表明，所有提出的配合物结构都是能量稳定且有利的，得到的结果与实验非常吻合。此外，通过MTT 法对MCF-7、Hela、A549 和HEK 细胞系进行了复合物的体外细胞毒性研究。发现复合体1和2对 MCF-7 细胞系具有显着的细胞毒性。通过光谱技术分析，这些复合物还显示出对 CT-DNA 和蛋白质（HSA 和 BSA）的强烈亲和力。通过各种染色、流式细胞术和通过 RT-PCR 获得的基因表达分析，对所选复合物的细胞死亡机制进行了进一步研究。

更新日期：2020-07-20

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