Development of the Selective NOS Inhibitors Based on Novel Reaction Mechanism

基于新型反应机制的选择性NOS抑制剂的研制

• 批准号: 12672063
• 负责人: OHSAWA Akio
• 金额: $ 2.18万
• 依托单位: SHOWA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672063/
• 关键词: nitvic oxide; azaaromatic; N-amino compound; NO scavenger; NOS inhibitor

Although nitric oxide (NO) plays a variety of roles in biological systems, formation of NO in high concentration causes cytotoxicity. Thus, it is necessary to develop chemicals which quench NO only when NO is produced excessively. For developing such chemicals, we have investigated the reaction of NO with various heterocyclic compounds and found that N-aminopyridinium perchlorate reacted with NO rapidly even in water and that NO was transformed to the form of N_<2O>. This finding suggests that NO is completely detoxified via this reaction. With this precedent in hand, we further investigated the reaction of various kinds of N-anminoazaaromatics with NO, and found most of all the compounds were good scavengers of NO. Moreover, it was found that these compounds were reacted with superoxide smoothly to quench this active oxygen species. Therefore, N-aminoazaaromatics were found to be good scavengers for both NO and superoxide, both of which play a criticai role in oxidative damage in biological systems. In addition, we also found that N-alkylazaaromatic quaternary salts functioned as activators of superoxide to oxidatively cleavage C=C double bond.

尽管一氧化氮 (NO) 在生物系统中发挥多种作用，但高浓度 NO 的形成会导致细胞毒性。因此，有必要开发仅当NO产生过量时才淬灭NO的化学品。为了开发此类化学品，我们研究了NO与各种杂环化合物的反应，发现高氯酸N-氨基吡啶鎓即使在水中也能与NO快速反应，并且NO转化为N_ 2O 的形式。这一发现表明，NO 通过该反应完全解毒。以此为先例，我们进一步研究了各种N-氨基氮杂芳烃与NO的反应，发现大多数化合物都是良好的NO清除剂。此外，还发现这些化合物能够顺利地与超氧化物反应以猝灭这种活性氧物质。因此，N-氨基氮杂芳香族化合物被发现是一氧化氮和超氧化物的良好清除剂，这两者在生物系统的氧化损伤中发挥着关键作用。此外，我们还发现N-烷基氮杂芳族季盐作为超氧化物的活化剂，氧化裂解C=C双键。

项目成果

A.Ohsawa., et al.: "Cleavage of S-S Bond by Nitric Oxide (NO) in the Presence of Oxygen : A Disproportionation Reaction of Two Disulfides"Chem. Pharm. Bull. 48. 1524-1528 (2000)

A.Ohsawa., et al.：“氧气存在下一氧化氮 (NO) 对 S-S 键的裂解：两个二硫化物的歧化反应”Chem.

T. Itoh, M. Miyazawaki, H. Maeta, Y. Mtsuya, K. Nagata, and A. Ohsawa: "Radical Scavenging by N-Aminoazaaromatics."Bioorg. Med. Cham.. 8. 1983-1989 (2000)

T. Itoh、M. Miyazawaki、H. Maeta、Y. Mtsuya、K. Nagata 和 A. Ohsawa：“N-氨基氮杂芳族化合物的自由基清除”。Bioorg。

A.Ohsawa., et al.: "Radical Scavenging by N-Aminoazaaromatics"Bioorg. Med. Chem. 8. 1983-1989 (2000)

A.Ohsawa.等人：“N-氨基氮杂芳香族化合物的自由基清除”Bioorg。

N. Tsutsumi, T. Itoh, and A. Ohsawa: "Cleveage of S-S Bond by Nitric Oxide(NO) in the Presence of Oxygen : A Didproportionation Reaction of Two Disulfides"Chem. Pharm. Bull.. 48. 1524-1528 (2000)

N. Tsutsumi、T. Itoh 和 A. Ohsawa：“氧气存在下一氧化氮 (NO) 裂解 S-S 键：两个二硫化物的双比例化反应”Chem。