MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.
J Inorg Biochem. 2021 Apr;217:111380. doi: 10.1016/j.jinorgbio.2021.111380. Epub 2021 Feb 3.
The antiproliferative activity of three cyclometalated Ru(II) complexes with the formula [Ru(bpy)L]PF, where bpy = 2,2'-bipyridine, Ru1: L1 = phenanthro[4,5-fgh]quinoxaline; Ru2: L2 = benzo[f]naphtho[2,1-h]quinoxaline; and Ru3: L3 = phenanthro[9,10-b]pyrazine, have been synthesized and characterized. The lipophilicity of the three Ru(II) complexes was modulated by the alteration of the planarity in the ligands of the complexes. With appropriate lipophilicity, Ru1-Ru3 exhibited mitochondrial accumulating property and cytotoxic activity against a spectrum of cancer cell lines. The underlying mechanism study indicated that these Ru(II) complexes can selectively accumulate in mitochondria and disrupt physiological processes, including the redox balance and energy generation in cancer cells. Elevation of iron content in triple-negative breast cancer (MDA-MB-231 cells) was observed after treatment with Ru(II) complexes, which may contribute to the production of reactive oxygen species (ROS) via Fenton reaction chemistry. Besides, the Ru(II) complexes decreased the intracellular glutathione (GSH) in cancer cells, leading to the failure in the cells to combat oxidative damage. Both of the mentioned processes contribute to the high oxidative stress and eventually lead to cancer cell death. On the other hand, Ru1-Ru3 significantly induced the depletion of adenosine triphosphate (ATP), causing disturbance of energy generation. Moreover, the results of wound-healing assay and transwell invasion assay, as well as the tube formation assay indicated the anti-migration and anti-angiogenesis properties of Ru1-Ru3. Our study demonstrated that these Ru(II) complexes are promising chemotherapeutic agents with oxidative stress induction and energy generation disturbance.
三种具有通式[Ru(bpy)L]PF 的金属环戊二烯基钌(II)配合物[Ru(bpy)L]PF 的增殖活性研究，其中 bpy = 2,2'-联吡啶，Ru1：L1 = 菲咯啉[4,5-fgh]喹喔啉；Ru2：L2 = 苯并[f]萘并[2,1-h]喹喔啉；Ru3：L3 = 菲咯啉[9,10-b]吡嗪，已经被合成和表征。三种 Ru(II)配合物的亲脂性通过改变配合物配体的平面性来调节。具有适当的亲脂性，Ru1-Ru3 表现出线粒体积累特性和对多种癌细胞系的细胞毒性活性。基础机制研究表明，这些 Ru(II)配合物可以选择性地积累在线粒体中，并破坏生理过程，包括癌细胞中的氧化还原平衡和能量产生。在用 Ru(II)配合物处理后，观察到三阴性乳腺癌（MDA-MB-231 细胞）中铁含量升高，这可能通过芬顿反应化学产生活性氧（ROS）。此外，Ru(II)配合物降低了癌细胞中的细胞内谷胱甘肽（GSH），导致细胞无法对抗氧化损伤。这两个过程都有助于产生高氧化应激，最终导致癌细胞死亡。另一方面，Ru1-Ru3 显著诱导三磷酸腺苷（ATP）的耗竭，导致能量产生紊乱。此外，划痕愈合试验、transwell 侵袭试验和管形成试验的结果表明 Ru1-Ru3 具有抗迁移和抗血管生成特性。我们的研究表明，这些 Ru(II)配合物是具有氧化应激诱导和能量产生干扰的有前途的化疗药物。
