权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基于超氧化物歧化酶活性的新型抗炎药的开发研究

基本信息

批准号：
62870105
负责人：
HIROBE Masaaki
金额：
$ 4.54万
依托单位：
Faculty of Pharmaceutical Sciences, University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1989
项目状态：
已结题

项目摘要

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

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。 SOD 提供了针对多种疾病的防御系统，其中 O^-_ 似乎发挥着重要作用，包括炎症、癌变和衰老。因此，测试 SOD 本身或修饰的 SOD 作为药物非常重要。有报道称 SOD 在临床环境中具有有益作用。然而，使用 SOD 很困难，因为它们很容易被肾脏清除，并且由于其分子量高而无法进入细胞。 SOD 活性位点上铜、锰和铁的存在促使许多研究人员寻找这些具有 SOD 活性的金属的低分子量复合物。尽管许多铜配合物在体外催化O^-_歧化，但它们的反应活性在活细胞中通常存在的螯合剂的体内减弱。有用的 SOD 模拟物应该能够穿过细胞膜，并且应该稳定、活跃且无毒。 Fridovich 及其同事最近报道，Mn-desferal 作为 SOD 模拟物在体内是有效的。很少有报道涉及含铁 SOD 模拟物。然而，与铜或锰相比，铁的毒性较低，因此我们制备了具有亲脂性和中性配体的新型铁络合物。在本报告中，我们展示了 Fe(II)-四-N,N,N',N'(2-吡啶基甲基)乙二胺 (Fe-TPEN) 和 Fe(III)-三[N-(2-吡啶甲基)-2-氨乙基]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-氨基乙基]胺(3MeTPAA)和三[(2-咪唑基)-2-氨基乙基]胺(TIAA)铁配合物也被报道具有较高的SOD活性(Fe-3MeTPAA和Fe-TIAA的浓度相当于1单位SOD(IC_<50>)= 分别比其他 Fe 和 Cu 络合物低 0.5 和 1.0 μM）。这些新型复合物可能具有治疗应用。该复合物的抗炎作用目前正在研究中。较少的