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Nitro-imidazole-based ruthenium complexes with antioxidant and anti-inflammatory activities
Journal of Inorganic Biochemistry ( IF 3.9 ) Pub Date : 2020-02-24 , DOI: 10.1016/j.jinorgbio.2020.111048
Greyce Luri Sasahara , Florêncio Sousa Gouveia Júnior , Raphael de Oliveira Rodrigues , Dávila Souza Zampieri , Said Gonçalves da Cruz Fonseca , Rita de Cássia Ribeiro Gonçalves , Brena Ramos Athaydes , Rodrigo Rezende Kitagawa , Flávia Almeida Santos , Eduardo Henrique Silva Sousa , Aparecida Tiemi Nagao-Dias , Luiz Gonzaga de França Lopes

Inflammation is a physiological process triggered in response to tissue damage, and involves events related to cell recruitment, cytokines release and reactive oxygen species (ROS) production. Failing to control the process duration lead to chronification and may be associated with the development of various pathologies, including autoimmune diseases and cancer. Considering the pharmacological potential of metal-based compounds, two new ruthenium complexes were synthesized: cis-[Ru(NO2)(bpy)2(5NIM)]PF6 (1) and cis-[RuCl(bpy)2(MTZ)]PF6 (2), where bpy = 2,2′-bipyridine, 5NIM = 5-nitroimidazole and MTZ = metronidazole. Both products were characterized by spectroscopic techniques, followed by Density Functional Theory (DFT) calculations in order to support experimental findings. Afterwards, their in vitro cytotoxic, antioxidant and anti-inflammatory activities were investigated. Compounds 1 and 2 presented expressive in vitro antioxidant activity, reducing lipid peroxidation and decreasing intracellular ROS levels with comparable effectiveness to the standard steroidal drug dexamethasone or α-tocopherol. These complexes showed no noticeable cytotoxicity on the tested cancer cell lines. Bactericidal assay against metronidazole-resistant Helicobacter pylori, a microorganism able to disrupt oxidative balance, unraveled compound 1 moderate activity over that strain. Beside this, it was able to inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) production as well as interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. This latter activity is remarkable, which has not been reported for other ruthenium-based complexes. Altogether, these results suggest cis-[Ru(NO2)(bpy)2(5NIM)]PF6 complex has potential pharmacological application as an anti-inflammatory agent that deserve further biological investigation.



中文翻译:

硝基咪唑基钌配合物,具有抗氧化和抗炎活性

炎症是响应组织损伤而触发的生理过程,涉及与细胞募集,细胞因子释放和活性氧(ROS)产生有关的事件。无法控制过程的持续时间会导致时间同步化,并且可能与包括自身免疫性疾病和癌症在内的各种病理的发展有关。考虑到金属基化合物的药理潜力,合成了两种新的钌配合物:顺式-[Ru(NO 2)(bpy)2(5NIM)] PF 61和顺式-[RuCl(bpy)2(MTZ) ] PF 62),其中bpy = 2,2'-联吡啶,5NIM = 5-硝基咪唑,MTZ =甲硝唑。两种产品均采用光谱技术进行表征,然后通过密度泛函理论(DFT)计算以支持实验结果。之后,研究了它们的体外细胞毒性,抗氧化剂和抗炎活性。化合物12表现出体外抗氧化活性,可降低脂质过氧化作用并降低细胞内ROS水平,其功效与标准甾体类药物地塞米松或α-生育酚相当。这些复合物在测试的癌细胞系上没有显示出明显的细胞毒性。对甲硝唑耐药的幽门螺杆菌的杀菌试验,一种能够破坏氧化平衡的微生物,没有破坏化合物1的活性。除此之外,它还能抑制白细胞介素6(IL-6)和肿瘤坏死因子-α(TNF-α)的产生以及白介素1β(IL-1β)和环氧合酶2(COX-2)的表达。脂多糖(LPS)刺激的RAW264.7巨噬细胞。后一种活性是显着的,其他钌基配合物尚未报道过。总之,这些结果表明,顺式-[Ru(NO 2)(bpy)2(5NIM)] PF 6复合物作为抗炎药具有潜在的药理应用,值得进一步的生物学研究。

更新日期:2020-02-25
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