Back to Search
Start Over
Dual Mechanisms of HNO Generation by a Nitroxyl Prodrug of the Diazeniumdiolate (NONOate) Class.
- Source :
-
Journal of the American Chemical Society . 11/24/2010, Vol. 132 Issue 46, p16526-16532. 7p. - Publication Year :
- 2010
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PRODRUGS
*NITRIC oxide
*ESTERASES
*MYOGLOBIN
*GLUTATHIONE
Subjects
Details
- Language :
- English
- ISSN :
- 00027863
- Volume :
- 132
- Issue :
- 46
- Database :
- Academic Search Index
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 55570691
- Full Text :
- https://doi.org/10.1021/ja106552p