Biometals ( IF 4.1 ) Pub Date : 2021-04-26 , DOI: 10.1007/s10534-021-00308-x Chanchal Sonkar 1 , Novina Malviya 2 , Nilima Sinha 3 , Attreyee Mukherjee 4 , Srimanta Pakhira 3, 5, 6 , Suman Mukhopadhyay 1, 2
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Abstract
Ruthenium-based metallotherapeutics is an interesting alternative for platinum complexes acting as anticancer agents after the entry of KP1019, NAMI-A, and TLD1339 in clinical trials. Herein, we have synthesized three new arene ruthenium(II)-tetrazole complexes viz. [Ru2(η6-p-cymene)2(2-pytz)2Cl2] (1), [Ru2(η6-p-cymene)2(3-pytz)Cl3] (2), [Ru2(η6-p-cymene)2(4-pytz)Cl3] (3) [2-pytzH = 2-pyridyl tetrazole; 3-pytzH = 3-pyridyl tetrazole; 4-pytzH = 4-pyridyl tetrazole] which have been characterized by different analytical techniques. To aid the understanding of the complex formation, reactions of the arene ruthenium(II) dimer with tetrazoles were investigated using the first principles-based Density Functional Theory (DFT) B3LYP method. Electronic structures, equilibrium geometries of the reactants and products with the first-order saddle points, reactions mechanism, the changes of enthalpy (∆H) and free energy (∆G), chemical stability, and reaction barriers of the complexes were computed using the B3LYP DFT approach. The in vitro cytotoxicity of these complexes was investigated by MTT assay on different cancer cell lines which reveal complex 2 as the most significant cytotoxic agent toward the HeLa cell line. The complexes have also shown a strong binding affinity towards CT-DNA and albumin proteins (HSA and BSA) as analyzed through spectroscopic techniques. Investigation of the mechanism of cell death by complex 2 was further performed by various staining techniques, flow cytometry, and gene expression analysis by RT-PCR. Inhibition of cell migration study has been also revealed the possibility of complex 2 to act as a prospective anti-metastatic agent.
Graphic abstract
中文翻译：
钌(II)-四唑配合物的选择性抗癌活性及其机理见解
摘要
在 KP1019、NAMI-A 和 TLD1339 进入临床试验后，基于钌的金属治疗剂是铂络合物作为抗癌剂的有趣替代品。在此，我们合成了三种新的芳烃钌 (II)-四唑配合物，即。[Ru 2 (η 6 - p -伞花烃) 2 (2-pytz) 2 Cl 2 ] ( 1 )、[Ru 2 (η 6 - p -伞花烃) 2 (3-pytz)Cl 3 ] ( 2 )、[ Ru 2 (η 6 - p -伞花烃) 2 (4-pytz)Cl 3 ] (3 ) [2-pytzH = 2-吡啶基四唑；3-pytzH = 3-吡啶基四唑；4-pytzH = 4-吡啶基四唑]已通过不同的分析技术进行了表征。为了帮助理解复合物的形成，使用基于第一原理的密度泛函理论 (DFT) B3LYP 方法研究了芳烃钌 (II) 二聚体与四唑的反应。电子结构、具有一阶鞍点的反应物和产物的平衡几何形状、反应机理、配合物的焓 (ΔH) 和自由能 (ΔG) 变化、化学稳定性和反应势垒使用B3LYP DFT 方法。这些复合物的体外细胞毒性通过 MTT 法对不同的癌细胞系进行了研究，揭示了复合物2作为对 HeLa 细胞系最重要的细胞毒剂。通过光谱技术分析，复合物还显示出对 CT-DNA 和白蛋白（HSA 和 BSA）的强结合亲和力。通过各种染色技术、流式细胞术和通过 RT-PCR 进行的基因表达分析，进一步研究了复合物2导致细胞死亡的机制。抑制细胞迁移的研究也揭示了复合物2作为一种预期的抗转移剂的可能性。
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