Department of Biosciences and Biomedical Engineering, School of Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore, MP, 453552, India.
Department of Chemistry, School of Basic Sciences, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore, MP, 453552, India.
Biometals. 2021 Aug;34(4):795-812. doi: 10.1007/s10534-021-00308-x. Epub 2021 Apr 26.
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. [Ru(η-p-cymene)(2-pytz)Cl] (1), [Ru(η-p-cymene)(3-pytz)Cl] (2), [Ru(η-p-cymene)(4-pytz)Cl] (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.
钌基金属疗法是继 KP1019、NAMI-A 和 TLD1339 进入临床试验后，作为抗癌药物的铂类配合物的一种有趣替代品。在此，我们合成了三种新型芳基钌（II）-四唑配合物，即[Ru(η-p-cymene)(2-pytz)Cl]（1）、[Ru(η-p-cymene)(3-pytz)Cl]（2）、[Ru(η-p-cymene)(4-pytz)Cl]（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]，并用不同的分析技术对其进行了表征。为了帮助理解配合物的形成，我们使用基于第一性原理的密度泛函理论（DFT）B3LYP 方法研究了芳基钌（II）二聚体与四唑的反应。用 B3LYP DFT 方法计算了电子结构、反应物和产物的平衡几何形状以及一阶鞍点、反应机理、焓变（∆H）和自由能变（∆G）、配合物的化学稳定性和反应势垒。通过 MTT 法在不同的癌细胞系上研究了这些配合物的体外细胞毒性，结果表明配合物 2 对 HeLa 细胞系具有最强的细胞毒性。通过光谱技术还表明，这些配合物对 CT-DNA 和白蛋白蛋白（HSA 和 BSA）具有很强的结合亲和力。通过各种染色技术、流式细胞术和 RT-PCR 的基因表达分析进一步研究了配合物 2 诱导细胞死亡的机制。抑制细胞迁移的研究也表明，配合物 2 有可能成为一种有前途的抗转移剂。
