HNO and NO Release from a Primary Amine-Based Diazeniumdiolate As a Function of pH

Abstract

The growing evidence that nitroxyl (HNO) has a rich pharmacological potential that differs from that of nitric oxide (NO) has intensified interest in HNO donors. Recently, the diazeniumdiolate (NONOate) based on isopropylamine (IPA/NO; Na[(CH3)2CHNH(N(O)NO)]) was demonstrated to function under physiological conditions as an organic analogue to the commonly used HNO donor Angeli’s salt (Na2N2O3). The decomposition mechanism of Angeli’s salt is dependent on pH, with transition from an HNO to an NO donor occurring abruptly near pH 3. Here, pH is shown to also affect product formation from IPA/NO. Chemical analysis of HNO and NO production led to refinement of an earlier, quantum mechanically based prediction of the pH-dependent decomposition mechanisms of primary amine NONOates such as IPA/NO. Under basic conditions, the amine proton of IPA/NO is able to initiate decomposition to HNO by tautomerization to the nitroso nitrogen (N2). At lower pH, protonation activates a competing pathway to NO production. At pH 8, the donor properties of IPA/NO and Angeli’s salt are demonstrated to be comparable, suggesting that at or above this pH, IPA/NO is primarily an HNO donor. Below pH 5, NO is the major product, while IPA/NO functions as a dual donor of HNO and NO at intermediate pH. This pH-dependent variability in product formation may prove useful in examination of the chemistry of NO and HNO. Furthermore, primary amine NONOates may serve as a tunable class of nitrogen oxide donor.

Glutathione sulfinamide serves as a selective, endogenous biomarker for nitroxyl after exposure to therapeutic levels of donors

“…DEA/NO, a related secondary amine NONOate, is commonly used to compare the selectivity of an assay for HNO over NO because it is a pure NO donor with respect to HNO 59 ( t ½ 2.1 min, pH 7.4, 37 °C) [41]. IPA/NO, a primary amine NONOate, decomposes to form both HNO and NO due to competing pH-dependent decomposition mechanisms ( t ½ 7 min, pH 7.4, 37 °C) [42] and has been used for evaluating concurrent release of both HNO and NO. Additionally, IPA/NO has proven amenable to alkylation to produce a neutral species, AcOM-IPA/NO, that releases HNO by either a hydrolytic or enzymatic pathway [43].…”

HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO˙

“…Further, the HNO donor studied here, IPA-NO, has been shown to release both HNO and NO˙, depending on the prevailing pH (9,35,52). In these previous studies at alkaline pH (e.g., pH 8 or higher), only HNO was detected, whereas at acidic pH (below pH 5), NO˙was the predominant species, with physiological pH considered to release both.…”

Analysis of the HNO and NO donating properties of alicyclic amine diazeniumdiolates

“…Evidence of diazeniumdiolate formation was verified by the presence of a 250 nm peak, characteristic of the [N(O)NO]-moiety [22]. The molar extinction coefficients for these compounds (7,900–8,700 M −1 cm −1 ) were in good agreement with those of other diazeniumdiolates (6,000–10,000 M −1 cm −1 ) [22,34,37,40,46]. Cyclobutylamine- and cyclopropylamine-based diazeniumdiolates could not be isolated as the sodium salts due to low stability.…”

“…Very recently, the unstable methylamine diazeniumdiolate was characterized and was trapped as the more stable O 2 -benzyl derivative [42]. Under physiological conditions, IPA/NO has a short half-life of 6.7 min [46] and generates HNO via a tautomerization pathway (Scheme 3) [46–48]. At lower pH, protonation of the nitroso oxygen, followed by tautomerization and N-N bond cleavage, leads to NO production.…”