Curtailing the Hydroxylaminobarbituric Acid–Hydantoin Rearrangement To Favor HNO Generation

Abstract

Due to its inherent reactivity, HNO must be generated in situ through the use of donor compounds. One of the primary strategies for the development of new HNO donors has been modifying hydroxylamines with good leaving groups. A recent example of this strategy is the (hydroxylamino)barbituric acid (HABA) class of HNO donors. In this case, however, an undesired intramolecular rearrangement pathway to the corresponding hydantoin derivative competes with HNO formation, particularly in the absence of chemical traps for HNO. This competitive non-HNO-producing pathway has restricted the development of the HABA class to examples with fast HNO release profiles at physiological pH and temperature (t(1/2) < 1 min). Herein, the factors that favor the rearrangement pathway have been examined and two independent strategies that protect against rearrangement to favor HNO generation have been developed. The timecourse and stoichiometry for the in vitro conversion of these compounds to HNO (trapped as a phosphine aza-ylide) and the corresponding barbituric acid (BA) byproduct have been determined by (1)H NMR spectroscopy under physiologically relevant conditions. These results confirm the successful extension of the HABA class of pure HNO donors with half-lives at pH 7.4, 37 °C ranging from 19 to 107 min.

Recent advances in the chemical biology of nitroxyl (HNO) detection and generation

“…84–86 The initial report reveals hydroxylamine-derived HNO donors based on Meldrum’s acid (t 1/2 =0.9 min), barbituric acid (t 1/2 =0.7 min) and pyrazolone (t 1/2 =9.5 min) that release HNO with high efficiency under physiological conditions without any enzymatic requirement. 84 Further modification of (hydroxylamino)-barbituric acid (HABA) successfully extended the half-lives of this new group of HNO donors from 19 to 107 min.…”

“…84 Further modification of (hydroxylamino)-barbituric acid (HABA) successfully extended the half-lives of this new group of HNO donors from 19 to 107 min. 86 An extensive investigation of the (hydroxylamino)- pyrazolone (HAPY) series shows these donors quantitatively produce HNO with half-lives spanning from minutes to days under physiological conditions. 86 In addition, this work shows the pyrazolone by-product reacts reversibly with HNO via an HNO-aldol reaction.…”

“…86 An extensive investigation of the (hydroxylamino)- pyrazolone (HAPY) series shows these donors quantitatively produce HNO with half-lives spanning from minutes to days under physiological conditions. 86 In addition, this work shows the pyrazolone by-product reacts reversibly with HNO via an HNO-aldol reaction. 85 These new structurally diverse HNO donors with extended half-lives hold promise as pharmacological tools and therapeutics.…”

Ring expansions of acyloxy nitroso compounds

“…6–13 Angeli’s salt (Na 2 N 2 O 3 ) and Piloty’s acid (PhSO 2 NHOH, N-hydroxy benzenesulfonamide) represent the most widely used HNO donors but numerous structurally and mechanistically diverse HNO donors have appeared, including acyloxy nitroso compounds. 14–19 While stable acyloxy nitroso compounds react as N-O heterodienophiles, 20 relatively little work describing their synthetic potential has appeared and we report two distinct ring expansions of acyloxy nitroso compounds.…”

Rapid Photoactivated Generation of Nitroxyl (HNO) under Neutral pH Conditions

“…To address this limitation, we have developed ap hotoactivatable HNO donor incorporating the (3-hydroxy-2-naphthalenyl)methyl phototrigger,which rapidly releases HNO on demand. [3] Thus,p recursor molecules (HNO donors) are required to generate HNO in situ for chemical and biological studies.Many HNO donors have been reported, [4] including Angeliss alt (AS), Pilotysa cid (PA) and related derivatives, [5] N-substituted hydroxylamines, [6] primary amine-based diazeniumdiolates, [7] acyloxy nitroso compounds, [8] precursors of acyl nitroso species, [9] and metal nitrosyls. [1] Furthermore HNO prodrugs show considerable promise as congestive heart failure therapeutics.…”