効率的なニトロキシル (HNO) ドナーとしてのN置換ヒドロキシラミンの開発
Daryl A Guthrie1, Nam Y Kim, Maxime A Siegler
1Department of Chemistry, 3400 North Charles Street, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Journal of the American Chemical Society
|January 12, 2012
まとめ
研究者らは,生理学的用途のために新しいニトロキシル (HNO) ドナー化合物を開発した. これらの新種のヒドロキシラミン誘導体は,生理学的条件下でHNOを効率的に放出し,潜在的な治療用途を提供しています.
科学分野:
- ケミストリー 化学
- バイオケミストリー バイオケミストリー
- 薬理学 薬理学とは
背景:
- ニトロキシル (HNO) は,治療の可能性のある反応性信号分子です.
- 既存のHNOドナー化合物は,数量と生理学的有用性において限られています.
- HNOの不安定性のために,HNOの局所生成は極めて重要です.
研究 の 目的:
- HNOドナーとしての新しいN置換ヒドロキシラミンを合成し,特徴づけること.
- 生理学的条件下でこれらの化合物からHNOの放出の効率と運動性を評価する.
- 制御されたHNO配信のための最適な離れるグループを特定する.
主な方法:
- 新種のN置換ヒドロキシアミンの合成.
- X線結晶学を用いた構造解明.
- pH 7.4 と 37 °C で HNO の放出に関する運動学的研究.
主要な成果:
- 新型ヒドロキシラミン誘導体の構造を成功裏に合成し確認した.
- 生理学的条件下で非酵素的なHNO生成が実証されています.
- バルビチューリック酸とピラゾロン誘導体を効率的なHNOドナーとして,それぞれ0.7分と9.5分の半減期で特定しました.
- HNOの放出率は,脱出するグループの性質に依存します.
結論:
- 新しいN代入型ヒドロキシラミンは,HNOドナーに対して in situ 効果があります.
- 脱出グループは,HNOの放出運動を著しく影響する.
- これらの化合物は,制御されたHNO投与を必要とする治療用途の有望な候補である.
関連する概念動画
01:261° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Overview
Nitrous acid and nitric acids are two types of acids containing nitrogen, among which nitrous acid is weaker than nitric acid. Nitrous acid with a pKa value of 3.37 ionizes in water to give a nitrite ion and the hydronium ion.
The nitrous acid is unstable. Hence, it is formed in situ from a solution of sodium nitrite and cold aqueous acids such as hydrochloric or sulfuric acid. In an acidic solution, the –OH group of nitrous acid undergoes protonation to give oxonium ion, followed by water loss...
The nitrous acid is unstable. Hence, it is formed in situ from a solution of sodium nitrite and cold aqueous acids such as hydrochloric or sulfuric acid. In an acidic solution, the –OH group of nitrous acid undergoes protonation to give oxonium ion, followed by water loss...
01:29Preparation of Amines: Reduction of Oximes and Nitro Compounds
Oximes can be reduced to primary amines using catalytic hydrogenation, hydride reduction, or sodium metal reduction. The reduction of aliphatic and aromatic nitro compounds to primary amines takes place by either catalytic hydrogenation or by using active metals like Fe, Zn, and Sn in the presence of an acid.
Though catalytic hydrogenation can reduce nitrobenzenes, the reduction is nonselective in the presence of other functional groups. For instance, if nitrobenzene contains an aldehyde group,...
Though catalytic hydrogenation can reduce nitrobenzenes, the reduction is nonselective in the presence of other functional groups. For instance, if nitrobenzene contains an aldehyde group,...
01:202° Amines to N-Nitrosamines: Reaction with NaNO2
Secondary amines react with nitrous acid to form N-nitrosamines, as depicted in Figure 1. Nitrous acid, a weak and unstable acid, is formed in situ from an aqueous solution of sodium nitrite and strong acids, such as hydrochloric acid or sulfuric acid, in cold conditions. In the presence of an acid, the nitrous acid gets protonated. The subsequent loss of water results in the formation of the electrophile known as nitrosonium ion.
01:371° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Mechanism
Nitrous acid is a relatively weak and unstable acid prepared in situ by the reaction of sodium nitrite and cold, dilute hydrochloric acid. In an acidic solution, the nitrous acid undergoes protonation when it loses water to form a nitrosonium ion—an electrophile. Nitrous acid reacts with primary amines to give diazonium salts. The reaction is called diazotization of primary amines.
01:19Diazonium Group Substitution: –OH and –H
Nitrous acid, a weak acid, is prepared in situ via the reaction of sodium nitrite with a strong acid under cold conditions. This nitrous acid prepared in situ reacts with primary arylamines to form arenediazonium salts. Such reactions are known as diazotization reactions. As shown in Figure 1, the formation of arenediazonium salts begins with the decomposition of nitrous acid in an acidic solution to give nitrosonium ions.
00:55Nitriles to Amines: LiAlH4 Reduction
Nitriles are reduced to amines in the presence of strong reducing agents like lithium aluminum hydride through a typical nucleophilic acyl substitution. The reaction requires two equivalents of the reducing agent. The reducing agent acts as a source of hydride ions.
As shown below, the mechanism involves three steps. Firstly, the hydride ion acting as a nucleophile attacks the nitrile carbon to form an anion. In the second step, a second equivalent of the hydride ion attacks the anion to...
As shown below, the mechanism involves three steps. Firstly, the hydride ion acting as a nucleophile attacks the nitrile carbon to form an anion. In the second step, a second equivalent of the hydride ion attacks the anion to...