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新型芳基钌(ii)咔唑基腙配合物的抗增殖活性和凋亡机制研究。

Investigation into antiproliferative activity and apoptosis mechanism of new arene Ru(ii) carbazole-based hydrazone complexes.

机构信息

Centre for Organometallic Chemistry, School of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu, India.

The First Affiliated Hospital, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China.

出版信息

Dalton Trans. 2020 Aug 18;49(32):11385-11395. doi: 10.1039/d0dt01476a.


DOI:10.1039/d0dt01476a
PMID:32776042
Abstract

Ruthenium complexes with bioactive ligands are becoming promising substitutes for platinum complexes due to their precise action against various cancers. In the present study, the synthesis of three new arene Ru(ii) complexes containing new carbazole-based hydrazone ligands of general formula [(η6-benzene)Ru(L)Cl] (1-3; L = carbazolone benzhydrazone ligands), and their anticancer properties are described. The structural characterization of the ligands and their ruthenium complexes has been realized with the aid of elemental analysis, IR, UV-vis, NMR and HR-MS techniques. The molecular structures of all three complexes have been elucidated by single crystal X-ray crystallography and reveal the existence of pseudo-octahedral geometry around the ruthenium. The in vitro cancer cell growth inhibition property of the complexes against A549 (lung carcinoma), A2780 (ovarian adenocarcinoma) and non-cancerous 16HBE (human lung bronchial epithelium) cells were examined by MTT assay. All the complexes display good cytotoxicity towards both of these types of cancer cell compared to the standard drug cisplatin, with low IC50 values. Remarkably, complex 3, which contains an electron-donating substituent, induces a significant reduction of viability in A2780 cells. The inhibition capacity of the complexes towards A2780 cells proliferation was further confirmed using 5-ethynyl-2-deoxyuridine (EdU) assay via minimal DNA synthesis. The result of the acridine orange-ethidium bromide (AO-EB) fluorescent staining assay establishes that the cytotoxicity of the complexes was mediated by apoptosis in cancer cells. Furthermore, flow cytometry using Annexin V-FITC/propidium iodide (PI) double staining determines the quantitative discrimination of early apoptosis by the externalization of phosphatidylserine. In addition, cell cycle distribution indicates that the complexes block the cell cycle progression in the S-phase. The outcome of our investigation shows the promising scope and potency of tailored arene ruthenium complexes for precise cancer chemotherapy beyond platinum drugs.

摘要

钌配合物与生物活性配体结合,由于其对各种癌症的精确作用,正在成为有前途的铂配合物替代品。在本研究中,合成了三种新型芳基 Ru(ii)配合物,它们含有新型咔唑基腙配体的通用式[(η6-苯)Ru(L)Cl](1-3;L=咔唑酮苯腙配体),并描述了它们的抗癌特性。配体及其钌配合物的结构表征是通过元素分析、IR、UV-vis、NMR 和 HR-MS 技术实现的。所有三种配合物的分子结构均通过单晶 X 射线晶体学阐明,并揭示了钌周围存在假八面体几何形状。通过 MTT 测定法研究了配合物对 A549(肺癌)、A2780(卵巢腺癌)和非癌细胞 16HBE(人肺支气管上皮细胞)的体外癌细胞生长抑制特性。与标准药物顺铂相比,所有配合物对这两种类型的癌细胞均显示出良好的细胞毒性,IC50 值较低。值得注意的是,含有供电子取代基的配合物 3 可显著降低 A2780 细胞的活力。通过最小化 DNA 合成,使用 5-乙炔基-2-脱氧尿苷(EdU)测定法进一步证实了配合物对 A2780 细胞增殖的抑制能力。吖啶橙-溴化乙锭(AO-EB)荧光染色测定的结果证实,复合物在癌细胞中的细胞毒性是通过细胞凋亡介导的。此外,使用 Annexin V-FITC/碘化丙啶(PI)双重染色的流式细胞术确定了通过磷脂酰丝氨酸的外化对早期凋亡的定量区分。此外,细胞周期分布表明,该复合物在 S 期阻止细胞周期进展。我们的研究结果表明,经过定制的芳基钌配合物具有超越铂类药物的精确癌症化疗的广阔前景和潜力。

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