Kinetic Studies of Hydralazine Reaction with Acetaldehyde

O’Donnell, John P.; Proveaux, Woodrow J.; K.H., Joseph

doi:10.1002/jps.2600681016

Cited by 10 publications

(4 citation statements)

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“…The reaction of hydralazine with low-molecular-weight aldehydes, including aldose sugars, has been reported to generate triazolo[3,4- a ]phthalazine products, via oxidative cyclization of an initial hydrazone. − Related reactions involving imines derived from the AP-aldehyde residue have been reported previously, , including the oxidative cyclization of an AP-indole hydrazone adduct to give a pyridazino[3,4- b ]indolium ring system . Here, we explored whether hydralazine-AP adduct 7 undergoes oxidative cyclization.…”

Section: Resultsmentioning

confidence: 96%

“…In vivo, there are a number of electrophilic ketones such as α-ketoglutarate, acetaldehyde, acetone, and pyruvate that can compete with abasic sites for reaction with hydralazine. , Indeed, the pyruvate hydrazone 5 is a major metabolite of hydralazine in humans (Scheme ). Hydrazone formation is reversible, and these various hydralazine hydrazones can exist in equilibrium.…”

Section: Discussionmentioning

confidence: 99%

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Ultrafast Reaction of the Drug Hydralazine with Apurinic/Apyrimidinic Sites in DNA Gives Rise to a Stable Triazolo[3,4-a]phthalazine Adduct

Islam,

Shim,

Melton

et al. 2024

Chem. Res. Toxicol.

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The clinically used antihypertensive agent hydralazine rapidly generates hydrazone-derived adducts by reaction with apurinic/apyrimidinic (also known as abasic or AP) sites in many different sequences of duplex DNA. The reaction rates are comparable to those of some AP-trapping reagents previously described as “ultrafast.” Initially, reversible formation of a hydrazone adduct is followed by an oxidative cyclization reaction that generates a chemically stable triazolo[3,4-a]phthalazine adduct. The net result is that the reaction of hydralazine with AP sites in duplex DNA yields a rapid and irreversible adduct formation. Although the hydrazone and triazolo[3,4-a]phthalazine adducts differ by only two mass units, it was possible to use MALDI–TOF-MS and ESI–QTOF–nanospray-MS to quantitatively characterize mixtures of these adducts by deconvolution of overlapping isotope envelopes. Reactions of hydralazine with the endogenous ketone pyruvate do not prevent the formation of the hydralazine-AP adducts, providing further evidence that these adducts have the potential to form in cellular DNA. AP sites are ubiquitous in cellular DNA, and rapid, irreversible adduct formation by hydralazine could be relevant to the pathogenesis of systemic drug-induced lupus erythematosus experienced by some patients. Finally, hydralazine might be developed as a probe for the detection of AP sites, the study of cellular BER, and marking the location of AP sites in DNA-sequencing analyses.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Ultrafast Reaction of the Drug Hydralazine with Apurinic/Apyrimidinic Sites in DNA Gives Rise to a Stable Triazolo[3,4-a]phthalazine Adduct

Islam,

Shim,

Melton

et al. 2024

Chem. Res. Toxicol.

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“…One of the major metabolic pathways was caused by formation of the cyclic metabolite M6 via intermediates M7 and M8. In some cases the products can rearrange to form new heterocyclic rings (O'Donnell et al, 1979;Nikolic et al, 2004). Acetaldehyde and hydrazine react to form a hydrazone (Schiff base), which cyclizes on oxidation to methyltriazolophthalazine.…”

Section: Biotransformation Of Tzb-30878mentioning

confidence: 99%

“…Acetaldehyde and hydrazine react to form a hydrazone (Schiff base), which cyclizes on oxidation to methyltriazolophthalazine. The kinetics of the reaction to form methyltriazolophthalazine has been studied at 37°C and other temperatures at physiological pH and concentrations (O'Donnell et al, 1979). In rats, a lidocaine metabolite reacts with the aldehyde to form a heterocyclic compound (Nelson et al, 1973), and acetaldehyde reacts with dopamine, resulting in pharmacologically active compounds (Collins et al, 1979).…”

Section: Biotransformation Of Tzb-30878mentioning

confidence: 99%

Biotransformation of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel 5-Hydroxytryptamine (5-HT)_1A Agonist/5-HT₃ Antagonist, in Human Hepatic Cytochrome P450 Enzymes

Minato

Suzuki²,

Asagarasu³

et al. 2008

Drug Metab Dispos

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Irritable bowel syndrome (IBS) is a common multifactorial disorder with a largely undefined etiology. Symptoms of IBS, such as abdominal pain and diarrhea, commonly develop and persist in patients who are in remission from other stress-related diseases. To develop a medication for patients with IBS, we focused on the properties of 5-hydroxytryptamine (5-HT) 1A agonism and 5-HT 3 antagonism and synthesized a novel compound, TZB-30878 (Fig. 1). This compound was expected to have anxiolytic action via 5-HT 1A agonism and to suppress intestinal motility and visceral hypersensitivity via 5-HT 3 antagonism. TZB-30878 was previously shown to exhibit potent and highly selective serotonin 5-HT 3 receptor antagonistic activities and also a high affinity for the 5-HT 1A receptor subtype that contributes to an overall therapeutic effect (Tamaoki et al., 2007). The pharmacokinetics and excretion of TZB-30878 have been studied in vivo in rats previously (unpublished data). The results indicated that TZB-30878 is rapidly absorbed following p.o. administration, distributed to almost all the organs including brain, and eliminated into feces via bile. However, there is very limited information regarding metabolism of TZB-30878.The objective of this study was to clarify the biotransformation of TZB-30878 in humans. We characterized the chemical structures of metabolites and identified the human hepatic cytochromes P450 (P450) responsible for the metabolism of TZB-30878. Materials and MethodsChemicals. Trifluoroacetic acid, Tris, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and ammonium acetate were purchased from Nacalai Tesque Inc. (Kyoto, Japan). ␣-Naphthoflavone, sulfaphenazole, quinidine hydrochloride, and diethyldithiocarbamic acid sodium salt (diethyldithiocarbamate) were purchased from Sigma-Aldrich (St. Louis, MO). ␤-NADP ϩ ,Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.107.018168.ABBREVIATIONS: IBS, irritable bowel syndrome; 5-HT, 5-hydroxytryptamine; 6,7,

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Modification of Metoclopramide GLC Assay: Application to Human Biological Specimens

Tam

Axelson

Ongley

1979

Journal of Pharmaceutical Sciences

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Kinetic Studies of Hydralazine Reaction with Acetaldehyde

Cited by 10 publications

References 9 publications

Ultrafast Reaction of the Drug Hydralazine with Apurinic/Apyrimidinic Sites in DNA Gives Rise to a Stable Triazolo[3,4-a]phthalazine Adduct

Ultrafast Reaction of the Drug Hydralazine with Apurinic/Apyrimidinic Sites in DNA Gives Rise to a Stable Triazolo[3,4-a]phthalazine Adduct

Biotransformation of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel 5-Hydroxytryptamine (5-HT)_1A Agonist/5-HT₃ Antagonist, in Human Hepatic Cytochrome P450 Enzymes

Modification of Metoclopramide GLC Assay: Application to Human Biological Specimens

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Kinetic Studies of Hydralazine Reaction with Acetaldehyde

Cited by 10 publications

References 9 publications

Ultrafast Reaction of the Drug Hydralazine with Apurinic/Apyrimidinic Sites in DNA Gives Rise to a Stable Triazolo[3,4-a]phthalazine Adduct

Ultrafast Reaction of the Drug Hydralazine with Apurinic/Apyrimidinic Sites in DNA Gives Rise to a Stable Triazolo[3,4-a]phthalazine Adduct

Biotransformation of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel 5-Hydroxytryptamine (5-HT)1A Agonist/5-HT3 Antagonist, in Human Hepatic Cytochrome P450 Enzymes

Modification of Metoclopramide GLC Assay: Application to Human Biological Specimens

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Product

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Biotransformation of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel 5-Hydroxytryptamine (5-HT)_1A Agonist/5-HT₃ Antagonist, in Human Hepatic Cytochrome P450 Enzymes