Bi Wei, Bi Yue, Gao Xiang, Li Pengfei, Hou Shanshan, Zhang Yanrong, Bammert Cathy, Jockusch Steffen, Legalley Thomas D, Michael Gibson K, Bi Lanrong
Second Hospital of HeBei Medical University, Shijiazhuang 050000, PR China.
Second Hospital of HeBei Medical University, Shijiazhuang 050000, PR China.
Bioorg Med Chem. 2017 May 1;25(9):2545-2568. doi: 10.1016/j.bmc.2017.03.033. Epub 2017 Mar 19.
Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.
线粒体氧化损伤会导致包括缺血/再灌注损伤在内的多种病理状况。因此，保护线粒体免受氧化损伤应具有治疗意义。在本研究中，我们设计并合成了一系列新型吲哚 - TEMPO 共轭物，这些共轭物在二甲苯诱导的小鼠耳水肿模型中表现出良好的抗炎特性。我们已经证明，这些化合物可以保护细胞免受模拟缺血/再灌注（s - I/R）诱导的活性氧（ROS）过量产生和线粒体功能障碍。此外，我们已经证明吲哚 - TEMPO 共轭物可以减轻啮齿动物因肠道 I/R 损伤而诱导的器官损伤。因此，我们提出这些吲哚 - TEMPO 共轭物的药理特性和作用机制涉及多种协同作用，包括通过脂质过氧化减少自由基产生的能力，这与 ROS 介导的炎症过程激活的相关减少有关。我们进一步推测，吲哚 - TEMPO 共轭物的保护作用部分在于维持最佳的线粒体功能。
