Physics Department, National Dong Hwa University, Hualien 97401, Taiwan.
Facultad de Medicina, Universidad de Atacama, Copayapu 485, Copiapo 1531772, Chile.
Int J Mol Sci. 2023 Jul 25;24(15):11896. doi: 10.3390/ijms241511896.
Cisplatin-based chemotherapy is a common regimen for bladder cancer, a life-threatening cancer with more than 500,000 new cases worldwide annually. Like many other metallodrugs, cisplatin causes severe side effects for its general toxicity. Organoruthenium is known for its structural stability, good anticancer activity, and possible low general toxicity. Here, we have prepared and characterized a series of water-soluble ruthenium-arene complexes with N,N'-chelating ligands: [Ru(II)-η-arene-(4,4'-(X)-2,2'-bipyridine)Cl]Cl (arene = -cymene, X = CH (), COOH (), COOCH (), COOCH (); arene = benzene, X = CH (), COOCH (), COOCH ()). These complexes are carefully characterized using single-crystal X-ray diffraction, UV-vis, IR, H NMR, and MALDI-TOF MS spectroscopy. Their DFT-calculated structural and thermodynamic properties are consistent with the experimental observations. Biophysicochemical studies of complex interaction with CTDNA and BSA supported by molecular docking simulations reveal suitable properties of - as anticancer agents. Cytotoxicities of - are evaluated on healthy human MCF-10a-breast epithelial and African green monkey Vero cells, and carcinoma human HepG-2-hepatic, T24-bladder, and EAhy-926-endothelial cells. All complexes exhibit much higher cytotoxicity for T24 than cisplatin. Particularly, and are also highly selective toward T24. Fluorescence imaging and flow cytometry demonstrate that and penetrate T24 cell membrane and induce early apoptosis at their respective IC concentrations, which ultimately lead to cell death. Statistical analysis suggests that the order of importance for T24 cell antiproliferation is protein binding, Log , Ru-Cl bond length, while DNA binding is the least important. This study is the first to report the anti-bladder cancer efficacy of Ru-arene-2,2'-bipyridine complexes, and may provide insights for rational design of organoruthenium drugs in the enduring search for new chemotherapeutic agents.
顺铂为基础的化疗是膀胱癌的常见治疗方案，膀胱癌是一种危及生命的癌症，全球每年有超过 50 万例新发病例。与许多其他金属药物一样，顺铂因其普遍的毒性而引起严重的副作用。有机钌因其结构稳定性、良好的抗癌活性和可能的低普遍毒性而闻名。在这里，我们制备并表征了一系列具有 N,N'-螯合配体的水溶性钌-芳环配合物：[Ru(II)-η-芳环-(4,4'-(X)-2,2'-联吡啶)]Cl]Cl（芳环=- 枯烯，X=CH()，COOH()，COOCH()，COOCH()；芳环=苯，X=CH()，COOCH()，COOCH()）。这些配合物使用单晶 X 射线衍射、紫外-可见、红外、H NMR 和 MALDI-TOF MS 光谱进行了仔细表征。它们的 DFT 计算结构和热力学性质与实验观察结果一致。通过分子对接模拟支持的与 CTDNA 和 BSA 的生物物理化学相互作用研究表明，具有作为抗癌剂的合适性质。-对健康人 MCF-10a-乳腺上皮和非洲绿猴 Vero 细胞以及人肝癌 HepG-2-肝、T24-膀胱和 EAhy-926-内皮细胞的细胞毒性进行了评估。所有配合物对 T24 的细胞毒性均明显高于顺铂。特别是，和也对 T24 具有高度选择性。荧光成像和流式细胞术表明，和能够穿透 T24 细胞膜，并在各自的 IC 浓度下诱导早期细胞凋亡，最终导致细胞死亡。统计分析表明，T24 细胞增殖抑制的重要性顺序为蛋白质结合、Log、Ru-Cl 键长，而 DNA 结合是最不重要的。这项研究首次报道了钌-芳环-2,2'-联吡啶配合物的抗膀胱癌功效，为合理设计有机钌药物提供了思路，有助于在不断寻找新的化疗药物的过程中。
