Development of <i>N</i>-Substituted Hydroxylamines as Efficient Nitroxyl (HNO) Donors

Guthrie, Daryl A.; Kim, Nam Y.; Siegler, Maxime A.; Moore, Cathy D.; Toscano, John P.

doi:10.1021/ja2103923

Cited by 46 publications

(50 citation statements)

References 35 publications

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“…27 Following the 1 H NMR assay described above, the observed half-life of HAPY-1 is reduced in half to 4 min, presumably due to minimization of the reverse reaction, PY-1 plus HNO to give HAPY-1 (Table 3).…”

Section: ■ Introductionmentioning

confidence: 98%

“Catch-and-Release” of HNO with Pyrazolones

Guthrie

Takahashi

et al. 2015

J. Org. Chem.

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A new and versatile class of HNO donors, the (hydroxylamino)pyrazolone (HAPY) series of HNO donors utilizing pyrazolone (PY) leaving groups, is described. HNO, the smallest N-based aldehyde equivalent, is used as a reagent along with a variety of PY compounds to synthesize the desired HAPY donors in what can be considered an N-selective HNO-aldol reaction in up to quantitative yields. The bimolecular rate constant of HNO with PY in pH 7.4 phosphate buffer at 37 °C can reach 8 × 10(5) M(-1) s(-1). In (1)H NMR experiments, the HAPY compounds generate HNO quantitatively (trapped as a phosphine aza-ylide) with half-lives spanning 3 orders of magnitude (minutes to days) under physiologically relevant conditions. B3LYP/6-31G* calculations confirm the energetically favorable reactions between HNO and the PY enol and enolate, whereas HNO release is expected to occur through the oxyanion (OHN-PY) of each HAPY compound. HNO has been shown to provide functional support to failing hearts.

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Section: ■ Introductionmentioning

confidence: 98%

“Catch-and-Release” of HNO with Pyrazolones

Guthrie

Takahashi

et al. 2015

J. Org. Chem.

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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%

“…The hydrolysis pathway remains dominant in the corresponding HAMA derivative with O-methyloxime substitution. 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.…”

Section: ■ Introductionmentioning

confidence: 99%

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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“…[8] In recent years, donors that release HNO photochemically [13], thermally [14], enzymatically [15], hydrolytically [16], or by oxidation [17] have been developed. Another HNO donor is N-hydroxybenzenesulfonamide (C 6 H 5 SO 2 NHOH, Piloty's acid, PA), which decomposes above pH 9 producing HNO through a base-catalyzed deprotonation mechanism, or releases NO upon oxidation [2,[18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%