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

超氧化物歧化酶(SODS)催化超氧化物(O^-_)转化为过氧化氢和氧气。超氧化物歧化酶为几种疾病提供了一种防御系统，在这些疾病中，O^-_似乎扮演着重要的角色，包括炎症、癌症和衰老。因此，重要的是要测试这样的SOD或作为药品的改性SOD。已经有关于SODS在临床环境中的有益作用的报道。然而，使用超氧化物歧化酶是困难的，因为它们很容易被肾脏清除，并且由于它们的高分子量而无法进入细胞。铜、锰和铁存在于超氧化物歧化酶的活性部位，导致许多研究人员寻找具有超氧化物歧化酶活性的这些金属的低分子络合物。虽然许多铜配合物在体外催化O^-__的歧化，但在体内它们的反应活性会被活细胞中常见的螯合剂减弱。有用的超氧化物歧化酶模拟物应该能够穿过细胞膜，并且应该是…更多的将是稳定的，活性和无毒的。Fridovich和他的同事最近报道了Mn-Desferal在活体中作为一种超氧化物歧化酶模拟物的有效性。很少有报道涉及含铁的超氧化物歧化酶模拟物。然而，与铜或锰相比，铁的毒性较低，这使得我们合成了具有亲脂性和中性配体的新型铁配合物。在本报告中，我们展示了Fe(Il)-四-N，N，N‘，N’-(2-吡啶甲基)乙二胺(Fe-TPEN)和Fe(III)-三[N-(2-吡啶甲基)-2-氨基乙基]胺(Fe-TPAA)的一些性质，它们具有较高的SOD活性，可以保护大肠杆菌免受百草枯的毒性。此外，三[N-(3-甲基-2-吡啶甲基)-2-氨基乙基]胺(3MeTPAA)和三[(2-咪唑基)-2-氨基乙基]胺(TIAA)的铁络合物也有较高的超氧化物歧化酶活性。Fe-3MeTPAA和Fe-TIAA相当于1单位超氧化物歧化酶(IC_(50)=0.5和1.0微米)比其他铁和铜的络合物。这些新的络合物可能具有治疗应用。这些复合体的抗炎作用目前正在研究中。较少

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