Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class

Daniela Andrei, Debra J. Salmon, Sonia Donzelli, Azadeh Wahab, John R. Klose, Michael L. Citro, Joseph E. Saavedra, David A. Wink, Katrina M Miranda, Larry K. Keefer

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)16526-16532
Number of pages7
JournalJournal of the American Chemical Society
Volume132
Issue number46
DOIs
StatePublished - Nov 24 2010

Fingerprint

Nitric oxide
Prodrugs
Nitric Oxide
Hydrolysis
Metmyoglobin
Lead compounds
Sarcomeres
Esterases
diazeniumdiolate
nitroxyl
Formaldehyde
Muscle Cells
Glutathione
Protons
Acetates
Nitrogen
Enzymes
Heart Failure
Salts
Ions

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Andrei, D., Salmon, D. J., Donzelli, S., Wahab, A., Klose, J. R., Citro, M. L., ... Keefer, L. K. (2010). Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class. Journal of the American Chemical Society, 132(46), 16526-16532. https://doi.org/10.1021/ja106552p

Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class. / Andrei, Daniela; Salmon, Debra J.; Donzelli, Sonia; Wahab, Azadeh; Klose, John R.; Citro, Michael L.; Saavedra, Joseph E.; Wink, David A.; Miranda, Katrina M; Keefer, Larry K.

In: Journal of the American Chemical Society, Vol. 132, No. 46, 24.11.2010, p. 16526-16532.

Research output: Contribution to journalArticle

Andrei, D, Salmon, DJ, Donzelli, S, Wahab, A, Klose, JR, Citro, ML, Saavedra, JE, Wink, DA, Miranda, KM & Keefer, LK 2010, 'Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class', Journal of the American Chemical Society, vol. 132, no. 46, pp. 16526-16532. https://doi.org/10.1021/ja106552p
Andrei, Daniela ; Salmon, Debra J. ; Donzelli, Sonia ; Wahab, Azadeh ; Klose, John R. ; Citro, Michael L. ; Saavedra, Joseph E. ; Wink, David A. ; Miranda, Katrina M ; Keefer, Larry K. / Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class. In: Journal of the American Chemical Society. 2010 ; Vol. 132, No. 46. pp. 16526-16532.
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AU - Klose, John R.

AU - Citro, Michael L.

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AU - Keefer, Larry K.

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