Orally active antioxidative copper(II) aspirinate: synthesis, structure characterization, superoxide scavenging activity, and in vitro and in vivo antioxidative evaluations
Orally active antioxidative copper(II) aspirinate: synthesis, structure characterization, superoxide scavenging activity, and in vitro and in vivo antioxidative evaluations
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DOI：
10.1007/s00775-005-0031-3
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发表时间：
2005-12-01
影响因子：
3
通讯作者：
Ishida, T
中科院分区：
文献类型：
--
作者：
Fujimori, T;Yamada, S;Ishida, T
自从活性氧（reactive oxygen species，ROS）被提出参与多种疾病的发病机制以来，超氧化物歧化酶（superoxidedismutase，SOD）模拟物的研究一直是热点。我们从Cu（II）和阿司匹林制备了铜（II）阿司匹林酸盐[Cu-2（asp）（4）]，其已作为解热剂、镇痛剂和抗炎剂使用多年。然而，已发现Cu-2（asp）（4）具有额外的活性，包括抗炎、抗溃疡、抗缺血/再灌注剂、抗癌、抗突变和抗微生物活性。还比较了水杨酸铜[Cu（sal）（2）]与Cu-2（asp）（4）的活性。用X射线结构分析确定了Cu-2（asp）（4）的结构。其SOD模拟活性测定使用细胞色素c，电子自旋共振（ESR）光谱，和ESR自旋陷阱方法。Cu-2（asp）（4）的活性略高于CuSO_4和醋酸铜[Cu（ace）（2）]，略低于Cu（sal）（2）。在紫外线B（UVB）照射后，根据细胞存活率，在人上皮细胞或转化的肿瘤性角质形成细胞、HaCaT和正常真皮成纤维细胞中评价了体外抗氧化活性，在Cu-2（asp）（4）、Cu（sal）（2）和CuSO 4存在下显著增加。此外，与溶剂或Cu（ace）（2）处理的小鼠相比，连续三天口服Cu-2（asp）（4）的无毛小鼠皮肤中UVA照射后的ROS产生显著抑制。在此基础上，Cu-2（asp）（4）被认为是一种具有抗氧化活性的化合物。总之，Cu-2（asp）（4）是一种有效的抗氧化剂，可用于未来治疗由ROS引起的疾病。
Ever since it was proposed that reactive oxygen species (ROS) are involved in the pathogeneses of various diseases, superoxide dismutase (SOD)-mimetic complexes have been intensively studied. We prepared copper(II) aspirinate [Cu-2(asp)(4)] from Cu(II) and aspirin, which has been in use for many years as an antipyretic, an analgesic, and an anti-inflammatory agent. However, Cu-2(asp)(4) has been found to have additional activities, including anti-inflammatory, antiulcer, anti-ischemic/reperfusion agent, anticancer, antimutagenic, and antimicrobial activities. The activity of copper salicylate [Cu(sal)(2)] was also compared with that of Cu-2(asp)(4). The structure of the Cu-2(asp)(4) was determined using X-ray structure analysis. Its SOD-mimetic activity was determined using cytochrome c, electron spin resonance (ESR) spectroscopy, and ESR spin trap methods. The activity of Cu-2(asp)(4) was slightly greater than CuSO4 and copper acetate [Cu(ace)(2)] and slightly less than that of Cu(sal)(2). The in vitro antioxidant activity, evaluated in human epithelial or transformed neoplastic keratinocyte cells, HaCaT, and normal dermal fibroblasts in terms of cell survival following ultraviolet B (UVB) irradiation, was significantly increased in the presence of Cu-2(asp)(4), Cu(sal)(2), and CuSO4. Further, ROS generation following UVA irradiation in the skin of hairless mice following oral treatment with Cu-2(asp)(4) for three consecutive days was significantly suppressed compared to the vehicle- or Cu(ace)(2)-treated mice. On the basis of these results, Cu-2(asp)(4) was observed to be a potent antioxidative compound possessing antioxidative activity in biological systems. In conclusion, Cu-2(asp)(4) is a potent antioxidative agent that may be useful for future treatment of diseases resulting from ROS.