Nitroxyl analogs as inhibitors of aldehyde dehydrogenase

Nagasawa, Hiromichi; Yost, Yul; Elberling, James A.; Shirota, Frances N.; DeMaster, Eugene G.

doi:10.1016/0006-2952(93)90026-s

Cited by 19 publications

(15 citation statements)

References 16 publications

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“…Nitrosobenzene (NB), a C -nitroso compound which cannot hydrolytically release HNO and Angeli’s salt-derived HNO (the simplest nitroso compound) both inhibit the thiol-containing enzyme ALDH (reported IC 50 values of 2.5 and 1.8 μM, respectively) [24, 25]. ALDH inhibition arises from a direct reaction of these nitroso compounds with the active site thiol (C302) resulting in inhibition characterized by both an irreversible and reversible (by DTT) component resulting from sulfinamide and disulfide modifications [25].…”

Section: Resultsmentioning

confidence: 99%

“…The increased water solubility of 4-5 and their structural simlarlity to C -nitroso compounds, which also react with thiols [24], allows evaluation with myoglobin (Mb), a heme protein, and aldehyde dehydrogenase (ALDH), a thiol containing protein, known HNO targets. in the presence of pig liver esterase (PLE) to enhance HNO release [11, 25, 26].…”

Section: Introductionmentioning

confidence: 99%

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Water soluble acyloxy nitroso compounds: HNO release and reactions with heme and thiol containing proteins

DuMond

Wright

King

2013

Journal of Inorganic Biochemistry

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Nitroxyl (HNO) has gained interest as a potential treatment of congestive heart failure through the ability of the HNO donor, Angeli’s salt (AS), to evoke positive inotropic effects in canine cardiac muscle. The release of nitrite during decomposition limits the use of AS requiring other HNO sources. Acyloxy nitroso compounds liberate HNO and small amounts of nitrite upon hydrolysis and the synthesis of the water-soluble 4-nitrosotetrahydro-2H-pyran-4-yl acetate and pivalate allows for pig liver esterase (PLE)-catalysis increasing the rate of decomposition and HNO release. The pivalate derivative does not release HNO, but the addition of PLE catalyzes hydrolysis (t1/2 = 39 min) and HNO formation (65% after 30 min). In the presence of PLE, this compound converts metmyoglobin (MetMb) to iron nitrosyl Mb and oxyMb to metMb indicating these compounds only react with heme proteins as HNO donors. The pivalate in the presence and the absence of PLE inhibits aldehyde dehydrogenase (ALDH) with IC50 values of 3.5 and 3.3 μM, respectively, in a time-dependent manner. Reversibility assays reveal reversible inhibition of ALDH in absence of PLE and partially irreversible inhibition with PLE. Liquid chromatography-mass spectrometry (LC-MS) reveals formation of a disulfide upon incubation of an ALDH peptide without PLE and a mixture of disulfide and sulfinamide in the presence of PLE. A dehydroalanine residue forms upon incubation of this peptide with excess AS. These results identify acyloxy nitroso compounds as unique HNO donors capable of thiol modification through direct electrophilic reaction or HNO release.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Water soluble acyloxy nitroso compounds: HNO release and reactions with heme and thiol containing proteins

DuMond

Wright

King

2013

Journal of Inorganic Biochemistry

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“…Para-substituted nitrosobenzenes react with the thiol groups of human Hb trapping these adducts within red blood cells (28). C-Nitroso compounds also inhibit ALDH through modification of the active site thiol (62). Taken together, these results clearly show that C-nitroso compounds react with thiols to yield oxidized sulfur products, and such reactivity may compete with the HNO-releasing properties of acyloxy nitroso compounds and demands further investigation.…”

Section: Alternative Reactionsmentioning

confidence: 87%

The Chemistry of Nitroxyl-Releasing Compounds

DuMond

King

2011

Antioxidants & Redox Signaling

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Nitroxyl (HNO) demonstrates a diverse and unique biological profile compared to nitric oxide, a redox-related compound. Although numerous studies support the use of HNO as a therapeutic agent, the inherent chemical reactivity of HNO requires the use of donor molecules. Two general chemical strategies currently exist for HNO generation from nitrogen-containing molecules: (i) the disproportionation of hydroxylamine derivatives containing good leaving groups attached to the nitrogen atom and (ii) the decomposition of nitroso compounds (X-N=O, where X represents a good leaving group). This review summarizes the synthesis and structure, the HNO-releasing mechanisms, kinetics and by-product formation, and alternative reactions of six major groups of HNO donors: Angeli's salt, Piloty's acid and its derivatives, cyanamide, diazenium diolate-derived compounds, acyl nitroso compounds, and acyloxy nitroso compounds. A large body of work exists defining these six groups of HNO donors and the overall chemistry of each donor requires consideration in light of its ability to produce HNO. The increasing interest in HNO biology and the potential of HNO-based therapeutics presents exciting opportunities to further develop HNO donors as both research tools and potential treatments.

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“…In contrast, NB, which is mostly monomeric, inhibited AlDH when administered to rats at one-fourth the molar dose of NA, as indicated by the dramatic increase in ethanol-derived blood acetaldehyde (AcH) levels, a reflection of the inhibition of hepatic mitochondrial AlDH-2. However, NB exhibited systemic toxicity even at this lower dose …”

Section: Introductionmentioning

confidence: 86%

“…Since nitroxyl is a highly reactive species that interacts readily with sulfhydryl groups and/or dimerizes to hyponitrous acid which in turn dehydrates to H 2 O and nitrous oxide (N 2 O), we postulated that N -aryl- or N -alkyl-substituted nitroxyls, viz., C - nitroso compounds , might represent stable forms that would inhibit AlDH directly without the need for bioactivation. Indeed, nitrosobenzene (NB) and 1-nitrosoadamantane (NA) were found to inhibit yeast AlDH with IC 50 values of 2.5 μM and 8.6 μM, respectively . The more sterically hindered 2-methyl-2-nitrosopropane (MNP) was several orders of magnitude less inhibitory (IC 50 = 150 μM), but none of these C -nitroso compounds required prior bioactivation to manifest AlDH inhibition.…”

Section: Introductionmentioning

confidence: 99%

Prodrugs of Nitroxyl and Nitrosobenzene as Cascade Latentiated Inhibitors of Aldehyde Dehydrogenase

et al. 1998

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The prototypic aromatic C-nitroso compound, nitrosobenzene (NB), was shown previously to mimic the effect of nitroxyl (HN=O), the putative active metabolite of cyanamide, in inhibiting aldehyde dehydrogenase (AlDH). To minimize the toxicity of NB in vivo, pro-prodrug forms of NB, which were designed to be bioactivated either by an esterase intrinsic to AlDH or the mixed function oxidase enzymes of liver microsomes, were prepared. Accordingly, the prodrug N-benzenesulfonyl-N-phenylhydroxylamine (3) was further latentiated by conversion to its O-acetyl (1a), O-methoxycarbonyl (1b), O-ethoxycarbonyl (1c), and O-methyl (2) derivatives. Similarly, pro-prodrug forms of nitroxyl were prepared by derivatization of the hydroxylamino moiety of methanesulfohydroxamic acid with N, O-bis-acetyl (7a), N,O-bis-methoxycarbonyl (7b), N, O-bis-ethoxycarbonyl (7c), and N-methoxycarbonyl-O-methyl (7d) groups. It was expected that the bioactivation of these prodrugs would initiate a cascade of nonenzymatic reactions leading to the ultimate liberation of NB or nitroxyl, thereby inhibiting AlDH. Indeed, the ester pro-prodrugs of both series were highly active in inhibiting yeast AlDH in vitro with IC50 values ranging from 21 to 64 microM. However, only 7d significantly raised ethanol-derived blood acetaldehyde levels when administered to rats, a reflection of the inhibition of hepatic mitochondrial AlDH-2.

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Nitroxyl analogs as inhibitors of aldehyde dehydrogenase

Cited by 19 publications

References 16 publications

Water soluble acyloxy nitroso compounds: HNO release and reactions with heme and thiol containing proteins

Water soluble acyloxy nitroso compounds: HNO release and reactions with heme and thiol containing proteins

The Chemistry of Nitroxyl-Releasing Compounds

Prodrugs of Nitroxyl and Nitrosobenzene as Cascade Latentiated Inhibitors of Aldehyde Dehydrogenase

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