| Project/Area Number |
62870105
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Faculty of Pharmaceutical Sciences, University of Tokyo |
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Principal Investigator |
HIROBE Masaaki Faculty of Pharmaceutical Sciences, University of Tokyo, Professor, 薬学部, 教授 (20012594)
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| Co-Investigator(Kenkyū-buntansha) |
OHZONO Shiro Eisai Co., Ltd., Director of R & D Division, 研究開発本部長
HIGUCHI Tsunehiko Faculty of Pharmaceutical Sciences, University of Tokyo, Assistant Professor, 薬学部, 助手 (50173159)
OHTA Shigeru Faculty of Pharmaceutical Sciences, University of Tokyo, Assistant Professor, 薬学部, 助手 (60160503)
NAGANO Tetsuo Faculty of Pharmaceutical Sciences, University of Tokyo, Associate Professor, 薬学部, 助教授 (20111552)
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| Project Period (FY) |
1987 – 1989
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| Project Status |
Completed (Fiscal Year 1989)
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| Budget Amount *help |
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1989: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1988: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1987: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Keywords | Superoxide / Superoxide dismutase / Iron Complex / Anti-inflammatory / 鉄金属錯体 / スーパーオキサイド / スーパーオキサイドディスムターゼ / 鉄・金属錯体 |
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| Research Abstract |
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
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