Studies on the Development of Novel Anti-inflammatory Based on Superoxide Dismutase Activity

超氧化物歧化酶（SOD）催化超氧化物（O^-）转化为过氧化氢和分子氧。超氧化物歧化酶提供了一种防御系统，可以抵抗几种疾病，其中O^-_似乎起着重要作用，包括炎症、致癌和衰老。因此，重要的是测试SOD本身或作为药物的改性SOD。有报告称SOD在临床环境中具有有益作用。然而，使用SOD是困难的，因为它们容易被肾脏清除，并且由于它们的高分子量而不能进入细胞。铜、锰和铁在SOD活性位点的存在导致许多研究者寻找具有SOD活性的这些金属的低分子量络合物。尽管许多铜配合物在体外能催化O^-_的歧化，但它们的反应性在体内会被活细胞中常见的螯合剂减弱。有用的SOD模拟物应该能够穿过细胞膜并且应该 关于我们 具有稳定、活性、无毒等特点。Fridovich等最近报道Mn-去铁醛在体内作为SOD模拟物是有效的，但关于含铁SOD模拟物的报道很少。然而，与铜或锰相比，铁的毒性较低，这促使我们制备具有亲脂性和中性配体的新型铁配合物。N'（2-吡啶基甲基）乙二胺（Fe-TPEN）和Fe（III）-三[N-（2-吡啶基甲基）乙二胺]（2-吡啶基甲基）-2-氨基乙基]胺（Fe-TPAA）具有高SOD活性，可以保护大肠杆菌细胞免受百草枯毒性。此外，三-[N-（3-甲基-2-吡啶基甲基）-2-氨乙基]胺（3 MeTPAA）和三[（2-咪唑基）-2-氨乙基]胺（TIAA）的铁配合物也被报道具有比其它Fe和Cu配合物更高的SOD活性（Fe-3 MeTPAA和Fe-TIAA的浓度相当于1个单位的SOD（IC）<50>分别为0.5和1.0 μ M）。这些新的配合物可能具有治疗应用。目前正在研究这些配合物的抗氧化作用。少

Superoxide dismutases (SODs) catalyze the conversion of superoxide (O^-_) to hydrogen peroxide plus dioxygen. SOD provides a defense system against several diseases in which O^-_ appears to play an important role, including inflammation, carcinogenesis and aging. It is therefore important to test SODs as such or modified SODs as pharmaceuticals. There have been reports of beneficial effects of SODs in clinical settings. It is difficult, however, to employ SODs because they are readily cleared by the kidney and are unable to enter cells because of their high molecular weight. The presence of copper, manganese, and iron at the active sites of SODs led many investigators to search for low molecular weight complexes of these metals having SOD activity. Although many copper complexes catalyze the dismutation of O^-_ in vitro, their reactivities are attenuated in vivo by chelating agents ordinarily found in living cells. Useful SOD mimics should be capable of crossing cell membranes and shou … More ld be stable, active and nontoxic. Fridovich and coworkers have recently reported that Mn-desferal is effective as an SOD mimic in vivo.Very little reported work deals with iron-containing SOD mimics. The low toxicity of iron in comparison with copper or manganese, however, led us to prepare novel iron complexes with lipophilic and neutral ligands.In this report, we show some of the properties of Fe(Il)-tetrakis-N,N,N',N'(2- pyridylmethyl)ethylenediamine (Fe-TPEN) and Fe(III)-tris[N-(2-pyridylmethyl)-2- aminoethyl]amine (Fe-TPAA) that have high SOD activity and can protect Escherichia coli cells from paraquat toxicity. In addition, both iron complexes of tris-[N-(3-methyl-2- pyridylmethy)-2-aminoethyl]amine (3MeTPAA) and tris[(2-imidazolyl)-2-aminoethyl]amine (TIAA) are also reported to have higher SOD activities (the conc. of Fe-3MeTPAA and Fe-TIAA equivalent to 1 unit of SOD (IC_<50>) = 0.5 and 1.0 muM, respectively) than other Fe and Cu complexes. These novel complexes may have therapeutic applications. The antiinflammatory effects of the complexes are now under investigation. Less