Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class.
Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class.
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DOI：
10.1021/ja106552p
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发表时间：
2010-11-24
影响因子：
15
通讯作者：
Keefer LK
中科院分区：
文献类型：
--
作者：
Andrei D;Salmon DJ;Donzelli S;Wahab A;Klose JR;Citro ML;Saavedra JE;Wink DA;Miranda KM;Keefer LK
在这里，我们描述了一种新的笼状形式的高度反应性的生物效应分子，硝酰基（HNO）。将结构为iPrHN−N（O）=NO−Na+（1，IPA/NO）的不稳定的一氧化氮（NO）和HNO生成盐与BrCH 2 OAc反应，产生结构为iPrHN − N（O）=NO− CH 2 OAc（2，AcOM-IPA/NO）的稳定衍生物，其在pH 7.4和37 °C下的水解速度比1慢一个数量级。2的水解生成HNO通过至少两种机制进行。在酯酶的存在下，直接解离为乙酸，甲醛和1是主导途径。在没有酶的情况下，游离1没有观察到作为中间体和NO的HNO的比例接近零的产品。为了解释这一令人惊讶的结果，我们提出了一种机制，其中碱诱导的2的N-H质子的去除导致乙酰基从氧迁移到相邻的氮，然后将所得重排产物裂解为异丙二氮离子和已知的HNO前体CH 3 −C（O）−NO。从2的HNO的可捕集产率在生理pH下显著增强超过1，部分原因是2的较慢水解速率产生了相应较低的HNO稳态浓度，因此，最大限度地减少了自消耗并增强了生物靶标如高铁肌红蛋白和谷胱甘肽的捕集。与化学捕获效率数据一致，前药2的微摩尔浓度显示出相对于1对从野生型小鼠心脏分离的心室肌细胞的显著更有效的肌节缩短作用，这表明2可能是用于开发心力衰竭疗法的有前景的先导化合物。
Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). Reacting the labile nitric oxide (NO)- and HNO-generating salt of structure iPrHN−N(O)=NO−Na+ (1, IPA/NO) with BrCH2OAc produced a stable derivative of structure iPrHN-N(O)=NO−CH2OAc (2, AcOM-IPA/NO), which hydrolyzed an order of magnitude more slowly than 1 at pH 7.4 and 37 °C. Hydrolysis of 2 to generate HNO proceeded by at least two mechanisms. In the presence of esterase, straightforward dissociation to acetate, formaldehyde, and 1 was the dominant path. In the absence of enzyme, free 1 was not observed as an intermediate and the ratio of NO to HNO among the products approached zero. To account for this surprising result, we propose a mechanism in which base-induced removal of the N−H proton of 2 leads to acetyl group migration from oxygen to the neighboring nitrogen, followed by cleavage of the resulting rearrangement product to isopropanediazoate ion and the known HNO precursor, CH3−C(O)−NO. The trappable yield of HNO from 2 was significantly enhanced over 1 at physiological pH, in part because the slower rate of hydrolysis for 2 generated a correspondingly lower steady-state concentration of HNO, thus, minimizing self-consumption and enhancing trapping by biological targets such as metmyoglobin and glutathione. Consistent with the chemical trapping efficiency data, micromolar concentrations of prodrug 2 displayed significantly more potent sarcomere shortening effects relative to 1 on ventricular myocytes isolated from wild-type mouse hearts, suggesting that 2 may be a promising lead compound for the development of heart failure therapies.
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影响因子：
1.8
作者：
Bohle, D. Scott;Keefer, Larry K.;Saavedra, Joseph E.
通讯作者：
Saavedra, Joseph E.
影响因子：
7.4
作者：
Lopez, Brenda E.;Shinyashiki, Masaru;Fukuto, Jon M.
通讯作者：
Fukuto, Jon M.
影响因子：
3.9
作者：
Lee, MJC;Shoeman, DW;Nagasawa, HT
通讯作者：
Nagasawa, HT
影响因子：
15
作者：
Cohen, AD;Zeng, BB;Toscano, JP
通讯作者：
Toscano, JP
影响因子：
7.3
作者：
LEE, MJC;NAGASAWA, HT;DEMASTER, EG
通讯作者：
DEMASTER, EG