“Catch-and-Release” of HNO with Pyrazolones

Guthrie, Daryl A.; Ho, Anthony D.; Takahashi, Cyrus; Collins, A. J.; Morris, Matthew J.; Toscano, John P.

doi:10.1021/jo502330w

Cited by 34 publications

(37 citation statements)

References 51 publications

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“…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.…”

Section: Advances In Hno Sourcesmentioning

confidence: 99%

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

Miao

King

2016

Nitric Oxide

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Nitroxyl or azanone (HNO) represents the redox-related (one electron reduced and protonated) relative of the well-known biological signaling molecule nitric oxide (NO). Despite the close structural similarity to NO, defined biological roles and endogenous formation of HNO remain unclear due to the high reactivity of HNO with itself, soft nucleophiles and transition metals. While significant work has been accomplished in terms of the physiology, biology and chemistry of HNO, important and clarifying work regarding HNO detection and formation has occurred within the last 10 years. This review summarizes advances in the areas of HNO detection and donation and their application to normal and pathological biology. Such chemical biological tools allow a deeper understanding of biological HNO formation and the role that HNO plays in a variety of physiological systems.

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Section: Advances In Hno Sourcesmentioning

confidence: 99%

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

Miao

King

2016

Nitric Oxide

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“…6,7 Piloty's acid (PA) and its derivatives, with sulfinate leaving groups, are classic examples of this strategy. 8−12 Piloty's acid itself is quite stable at pH 7.4 (t 1/2 > 1 h) but under physiological conditions can be oxidized, presumably to the corresponding nitroxide, and become an NO donor.…”

Section: ■ Introductionmentioning

confidence: 99%

“…6 However, the HAPY class is resistant to alternative non-HNO producing mechanisms, and the first series extension of this class is the subject of a companion paper. 7 Accessing longer lived HNO donors with half-lives on the order of minutes to hours, particularly within the same donor class, is expected to have a broad impact on optimizing HNO release rate for the treatment of any number of potential diseases, including congestive heart failure, alcoholism, vascular dysfunction, and cancer. Furthermore, sustained release of low concentrations of HNO might be an important step to mimic hypothesized endogenous HNO generation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…7 Moreover, this assay can be used to monitor the timecourse and stoichiometry of the HNO donor, the released byproduct, and HNO itself. The reaction scheme for the conversion of HABA-1−HABA-6 to BA-1−BA-6 and HNO (trapped as one molecule of an aza-ylide and one molecule of a phosphine oxide) is shown in Table 3.…”

Section: ■ Introductionmentioning

confidence: 99%

“…7 When R 1 = H (HABA-6), enolate formation on the barbituric acid ring slows the overall rate of HNO generation and inhibits rearrangement (vide infra). Rearrangement Studies.…”

Section: ■ Introductionmentioning

confidence: 99%

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Curtailing the Hydroxylaminobarbituric Acid–Hydantoin Rearrangement To Favor HNO Generation

et al. 2015

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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.

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

et al. 2016

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Directly obtaining kinetic and mechanistic data for the reactions of nitroxyl (HNO) with biomolecules (k % 10 3 -10 7 m À1 s À1 )i sn ot feasible for many systems because of slow HNO release from HNO donor molecules (t 1/2 is typically minutes to hours). 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. A" proof of concept" study is reported, which demonstrates that, upon continuous xenon light excitation, rapid decomposition of the HNO donor occurs within seconds.T he amount of HNO generated is strongly dependent on solvent and the rate of the reaction is dependent on the light intensity.Nitroxyl (HNO,n itrosyl hydride) is attracting increasing attention because it has chemical and biological properties distinct from the more widely studied nitric oxide (NO). [1] Furthermore HNO prodrugs show considerable promise as congestive heart failure therapeutics. [2] However,understanding the biological roles of HNO has been hindered by its propensity to dimerize rapidly in aqueous solution (k = 8 10 6 m À1 s À1 ). [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. [10] Although HNO donors are widely used in biochemical studies, [4,9d] factors limiting their utility include requiring alkaline (pH > 9) conditions to trigger HNO release, [4a, 11] and NO release at neutral pH conditions. [7c, 8a, 9b,c] Most importantly,in terms of mechanistic studies of HNO with biomolecules, HNO generation is invariably the rate-determining step, [12] since HNO reacts rapidly with biomolecules (k % 10 3 -10 7 m À1 s À1 ) [13] but is typically released more slowly (t 1/2 ca.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.

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“Catch-and-Release” of HNO with Pyrazolones

Cited by 34 publications

References 51 publications

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

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

Curtailing the Hydroxylaminobarbituric Acid–Hydantoin Rearrangement To Favor HNO Generation

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

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