Organometallic η⁶-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N’ heterocyclic and η⁶-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common “three-legged piano-stool” pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV–Visible absorption spectra in PBS buffer or DMSO over 24 h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV–Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 10⁴ M⁻¹. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA’s minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC₅₀ values in the range of 59.2–39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes.

Graphical abstract

Molecular docking simulations visualized the interactions of arene Ru(II) complexes with CT-DNA via minor grooving. The trends were corroborated by electrochemical and cytotoxicity data.

中文翻译：

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单核 η6-芳烃钌 (II) 与吡唑基-哒嗪配体的配合物：合成、CT-DNA 结合、谷胱甘肽反应性和细胞毒性

有机金属 η ⁶ -芳烃钌 (II) 与 3-氯-6-(1 H-吡唑-1-基)哒嗪（Ru1、Ru2和Ru5）和 3-氯-6-(3,5-二甲基-合成了1H-吡唑-1-基)哒嗪( Ru3-4 ) N ,N'杂环和η ^{6 -}芳烃(伞花烃( Ru1-4 )或甲苯( Ru 5 ) )。钌(II)配合物具有常见的“三足琴凳”伪八面体结构，以半三明治配合物而闻名。24 小时内，它们在 PBS 缓冲液或 DMSO 中的紫外-可见吸收光谱的演变证实了它们良好的溶剂分解稳定性。使用紫外-可见吸收和荧光光谱监测小牛胸腺 DNA (CT-DNA) 复合物的滴定。该复合物与CT-DNA 适度相互作用，其结合常数约为10 ⁴  M ^-1。复合物与 DNA-Hoechst 33,258 的竞争性结合描述了 Hoechst 从 DNA 小沟中的竞争性置换。这些复合物通过取代卤化物通过S配位与谷胱甘肽结合形成GSH加合物，其中碘类似物具有比氯复合物更高的结合常数。配合物的循环伏安图显示出一种电子转移准可逆过程。Ru1-5 /DNA分子对接数据的趋势与 DNA 结合常数的趋势相似。在这五种中，只有Ru1、Ru3和Ru5对 MCF-7 乳腺癌细胞表现出一定的活性（中等），IC ₅₀值在 59.2-39.9 范围内，其中Ru5的活性最强。然而，更难治疗的细胞系 MDA-MB 231 细胞对这些复合物的治疗表现出顽抗。

图形概要

分子对接模拟通过小凹槽可视化芳烃 Ru(II) 复合物与 CT-DNA 的相互作用。电化学和细胞毒性数据证实了这一趋势。